Systems and methods for aneurysm treatment

ABSTRACT

Disclosed herein is a method of producing high purity pentagalloyl glucose (PGG), analogues or derivatives thereof, at least 99.9% pure, by washing with dimethyl ether. PGG may be provided in a kit, including a hydrolyzer for dissolving the PGG and a saline solution. Also disclosed herein is a device for delivery of a therapeutic solution to a blood vessel. The device may be a catheter having an upstream balloon and a downstream balloon. The upstream balloon may be expanded to anchor the catheter and occlude antegrade blood flow. The downstream balloon may be expanded to occlude retrograde blood flow, creating a sealed volume within the blood vessel. The downstream balloon may have pores configured to deliver a therapeutic inflation solution into the sealed volume or a portion thereof. The downstream balloon may be expanded by the expansion of a balloon disposed inside the downstream balloon.

RELATED APPLICATIONS

This application is a continuation of PCT/US2019/024140 filed Mar. 26,2019, which claims the priority benefit of US Provisional ApplicationNo. 62/714,346 filed Aug. 3, 2018, the entire content of each of whichis hereby incorporated by reference herein in its entirety.

BACKGROUND

One of the most common results of the degradation of vasculature isaneurysm. By definition, the term “aneurysm” is simply an abnormalwidening or ballooning at the wall of a blood vessel. Aneurysms aredegenerative diseases characterized by destruction of arterialarchitecture and subsequent dilatation of the blood vessel that mayeventually lead to fatal ruptures. Some common locations for aneurysmsinclude the abdominal aorta (abdominal aortic aneurysm, AAA), thoracicaorta, and brain arteries. In addition, peripheral aneurysms of the leg,namely the iliac, popliteal and femoral arteries are prevalent locationsof this vascular pathology. The occurrence of such peripheral aneurysmsappears to be strongly associated with the presence of aneurysms inother locations, as it has been estimated that 30 to 60% of peripheralaneurysm patients also have an AAA.

Aneurysms can be devastating due to the potential for rupture ordissection that can lead to massive bleeding, stroke, or hemorrhagicshock, and can be fatal in an estimated 80% of cases. Aneurysms can becaused by any of a large class of degenerative diseases and pathologiesincluding atherosclerotic disease, defects in arterial components,genetic susceptibilities, and high blood pressure, among others, and candevelop silently over a period of years. The hallmarks of aneurysmsinclude enzymatic degradation of vascular structural proteins such aselastin, collagen, inflammatory infiltrates, calcification, and eventualoverall destruction of the vascular architecture. Elastin content in ananeurysmal aorta can be greatly reduced (for example, 70% less) thanthat of a healthy, undamaged aorta.

Aneurysms grow over a period of years and pose great risks to health.Aneurysms have the potential to dissect or rupture, causing massivebleeding, stroke, and hemorrhagic shock, which can be fatal in more than80% of cases. AAAs are a serious health concern, specifically for theaging population, being among the top ten causes of death for patientsolder than 50. The estimated incidence for abdominal aortic aneurysm isabout 50 in every 100,000 persons per year. Approximately 50,000operations are performed each year in the U.S. for AAAs alone. Inchildren, AAAs can result from blunt abdominal injury or from Marfan'ssyndrome, a defect in elastic fiber formation in walls of majorarteries, such as the aorta.

Current methods of treatment for diagnosed aneurysms are limited toinvasive surgical techniques. After initial diagnosis of a smallaneurysm, the most common medical approach is to follow up thedevelopment of the aneurysm and after reaching a pre-determined size(for example, about 5 cm in diameter), surgical treatment is applied.Current surgical treatments are limited to either an endovascular stentgraft repair or optionally complete replacement of the diseased vesselwith a vascular graft. While such surgical treatments can save lives andimprove quality of life for those suffering aneurysms, dangers beyondthose of the surgery itself still exist for the patient due to possiblepost-surgery complications (for example, neurological injuries,bleeding, or stroke) as well as device-related complications (forexample, thrombosis, leakage, or failure). Moreover, depending upon thelocation of the aneurysm, the danger of an invasive surgical proceduremay outweigh the possible benefits of the procedure, for instance in thecase of an aneurysm deep in the brain, leaving the sufferer with verylittle in the way of treatment options. Moreover, surgical treatmentsmay not always provide a permanent solution, as vascular grafts canloosen and dislodge should the aneurysm progress following thecorrective surgery. For some patients, the particular nature of theaneurysm or the condition of the patient makes the patient unsuitablefor graft repair.

Aneurysm is not the only condition for which enzymatic degradation ofstructural proteins is a hallmark. Other conditions in which structuralprotein degradation appears to play a key role include Marfan syndrome,supravalvular aortic stenosis. For those afflicted, such conditions leadto, at the very least, a lowered quality of life and often, prematuredeath.

Phenolic compounds are a diverse group of materials that have beenrecognized for use in a wide variety of applications. For instance, theynaturally occur in many plants, and are often a component of the humandiet. Phenolic compounds have been examined in depth for efficacy asfree radical scavengers and neutralizers, for instance in topical skinapplications and in food supplements. Phenolic compounds are alsobelieved to prevent cross-linking of cell membranes found in certaininflammatory conditions and are believed to affect the expressions ofspecific genes due to their modulation of free radicals and otheroxidative species (see, for example, U.S. patent application Ser. No.6,437,004 to Perricone).

What is needed in the art are treatment protocols and compositions forstabilization of the organs and tissues affected by degenerativeconditions such as aneurysm. In particular, treatment protocolsutilizing phenolic compounds could provide a safe, less invasive routefor the stabilization of the structural architecture in order to tempergrowth and/or development of such conditions.

SUMMARY

Some embodiments provide a composition comprising a compound of thefollowing Formula:

or a pharmaceutically acceptable salt thereof,

wherein: R¹-R¹⁹ have any of the values described herein, and wherein thecomposition is substantially free of gallic acid or methyl gallate. Insome embodiments, substantially free is less than about 0.5% gallicacid. In some embodiments, substantially free is less than about 0.5%methyl gallate.

In some embodiments, R¹, R², R³ and R⁴ are each independently hydrogenor R_(A);

-   -   R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸        and R¹⁹ are each independently hydrogen or R^(B);    -   each R^(A) is independently selected from the group consisting        of —OR^(X), —N(R^(Y))₂, halo, cyano, —C(═X)R^(Z),        —C(═X)N(R^(Y))₂, —C(═X)OR^(X), —OC(═X)R^(Z), —OC(═X)N(R^(Y))₂,        —OC(═X)OR^(X), —NR^(Y)C(═X)R^(Z), —NR^(Y)C(═X)N(R^(Y))₂,        —NR^(Y)C(═X)OR^(X), unsubstituted C₁₋₁₂alkoxy, substituted        C₁₋₁₂alkoxy, unsubstituted C₁₋₈alkyl, substituted C₁₋₈alkyl,        unsubstituted C₆ or ioaryl, substituted C₆ or ioaryl,        unsubstituted C₇₋₁₂aralkyl, substituted C₇₋₁₂aralkyl,        unsubstituted 5-10 membered heteroaryl, substituted 5-10        membered heteroaryl, unsubstituted C₃₋₁₂ heteroaralkyl,        substituted C₃₋₁₂heteroaralkyl, unsubstituted 3-10 membered        heterocyclyl, and substituted 3-10 membered heterocyclyl;    -   each R^(B) is independently selected from the group consisting        of —C(═X)R^(Z), —C(═X)N(R^(Y))₂, —C(═X)OR^(X), unsubstituted        C₁₋₈alkyl, substituted C₁₋₈alkyl, unsubstituted C₆ or ioaryl,        substituted C₆ or ioaryl, unsubstituted C₇₋₁₂aralkyl,        substituted C₇-uaralkyl, unsubstituted 5-10 membered heteroaryl,        substituted 5-10 membered heteroaryl, unsubstituted 3-10        membered heterocyclyl and substituted 3-10 membered        heterocyclyl, or two adjacent R^(B) groups together with the        atoms to which they are attached form an unsubstituted 3-10        heterocyclyl, a substituted 3-10 heterocyclyl, unsubstituted        5-10 membered heteroaryl ring or substituted 5-10 membered        heteroaryl ring;    -   each X is independently oxygen (O) or sulfur (S);    -   each R^(X) and R^(Y) is independently selected from the group        consisting of hydrogen, unsubstituted C₁₋₈alkyl, substituted        C₁₋₈alkyl, unsubstituted C₆ or ioaryl, substituted C₆ or ioaryl,        unsubstituted C₇₋₁₂aralkyl, substituted C₇₋₁₂aralkyl,        unsubstituted 5-10 membered heteroaryl, substituted 5-10        membered heteroaryl, unsubstituted 3-10 membered heterocyclyl        and substituted 3-10 membered heterocyclyl; and    -   each R^(Z) is independently selected from the group consisting        of unsubstituted C₁₋₁₂alkoxy, substituted C₁₋₁₂alkoxy,        unsubstituted C₁₋₈alkyl, substituted C₁₋₈alkyl, unsubstituted        C_(6 or 10)aryl, substituted C_(6 or 10)aryl, unsubstituted        C₇₋₁₂aralkyl, substituted C₇₋₁₂aralkyl, unsubstituted 5-10        membered heteroaryl, substituted 5-10 membered heteroaryl,        unsubstituted 3-10 membered heterocyclyl and substituted 3-10        membered heterocyclyl.

In some embodiments, at least one of R¹, R², R³ and R⁴ is R^(A). In someembodiments, at least two of R¹, R², R³ and R⁴ are R^(A). In someembodiments, each R^(A) is independently selected from the groupconsisting of —OR^(X), —N(R^(Y))₂, halo, cyano, —C(═X)R^(Z),—C(═X)N(R^(Y))₂, —C(═X)OR^(X), —OC(═X)R^(Z), —OC(═X)N(R^(Y))₂,—OC(═X)OR^(X), —NR^(Y)C(═X)R^(Z), —NR^(Y)C(═X)N(R^(Y))₂, and—NR^(Y)C(═X)OR^(X). In some embodiments, each R^(A) is independentlyselected from the group consisting of unsubstituted C₁₋₈alkoxy,substituted C₁₋₈alkoxy, unsubstituted C₁₋₈alkyl, substituted C₁₋₈alkyl,unsubstituted C_(6 or 10)aryl, substituted C_(6 or 10)aryl,unsubstituted C₇₋₁₂aralkyl, substituted C₇₋₁₂aralkyl, unsubstituted 5-10membered heteroaryl, substituted 5-10 membered heteroaryl, unsubstitutedC₃₋₁₂ heteroaralkyl, substituted C₃₋₁₂heteroaralkyl, unsubstituted 3-10membered heterocyclyl, and substituted 3-10 membered heterocyclyl. Insome embodiments, each R^(A) is independently selected from the groupconsisting of unsubstituted C₁₋₁₂alkoxy, unsubstituted C₁₋₈alkyl,unsubstituted C_(6 or 10)aryl, unsubstituted C₇₋₁₂aralkyl, unsubstituted5-10 membered heteroaryl, unsubstituted C₃₋₁₂ heteroaralkyl, andunsubstituted 3-10 membered heterocyclyl. In some embodiments, R¹, R²,R³ and R⁴ are each hydrogen. In some embodiments, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are each hydrogen.In some embodiments, at least one of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ is R^(B). In some embodiments, atleast two of R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷,R¹⁸ and R¹⁹ are R^(B). In some embodiments, at least three of R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ areR^(B). In some embodiments, each R^(B) is independently selected fromthe group consisting of unsubstituted C₁₋₁₂alkoxy, substitutedC₁₋₁₂alkoxy, unsubstituted C₁₋₈alkyl, substituted C₁₋₈alkyl,unsubstituted C₆ or ioaryl, substituted C₆ or ioaryl, unsubstitutedC₇₋₁₂aralkyl, substituted C₇₋₁₂aralkyl, unsubstituted 5-10 memberedheteroaryl, substituted 5-10 membered heteroaryl, unsubstituted C₃₋₁₂heteroaralkyl, substituted C₃₋₁₂heteroaralkyl, unsubstituted 3-10membered heterocyclyl, and substituted 3-10 membered heterocyclyl. Insome embodiments, each R^(B) is independently selected from the groupconsisting of unsubstituted C₁₋₁₂alkoxy, unsubstituted C₁₋₈alkyl,unsubstituted C_(6 or 10)aryl, unsubstituted C₇₋₁₂aralkyl, unsubstituted5-10 membered heteroaryl, unsubstituted C₃₋₁₂ heteroaralkyl, andunsubstituted 3-10 membered heterocyclyl. In some embodiments, twoadjacent R^(B) groups together with the atoms to which they are attachedform an unsubstituted 3-10 heterocyclyl, a substituted 3-10heterocyclyl, unsubstituted 5-10 membered heteroaryl ring or substituted5-10 membered heteroaryl ring.

In some embodiments, the pharmaceutical composition is formulated foradministration: orally, intraadiposally, intraarterially,intraarticularly, intracranially, intradermally, intralesionally,intramuscularly, intranasally, intraocularly, intrapericardially,intraperitoneally, intrapleurally, intraprostatically, intrarectally,intrathecally, intratracheally, intratumorally, intraumbilically,intravaginally, intravenously, intravesicularlly, intravitreally,liposomally, locally, mucosally, parenterally, rectally,subconjunctival, subcutaneously, sublingually, topically, transbuccally,transdermally, vaginally, in crèmes, in lipid compositions, via acatheter, via a lavage, via continuous infusion, via infusion, viainhalation, via injection, via local delivery, or via localizedperfusion. The pharmaceutical composition may be formulated for oral,topical, intravenous, or intravitreal administration. In someembodiments, the pharmaceutical composition is formulated as a unitdose.

In yet another aspect, the present disclosure provides methods oftreating and/or preventing a disease or a disorder in a patient in needthereof, comprising administering to the patient a composition describedherein in an amount sufficient to treat and/or prevent the disease ordisorder. In some embodiments, the present disclosure provides methodsof treating aneurysms.

Some embodiments provide a method of purifying a compound of Formula (I)comprising: washing a mixture with a solvent to remove substantially allgallic acid or methyl gallate. In some embodiments, the solvent isdiethyl ether. In some embodiments, the solvent is selected from thegroup consisting of methanol, toluene, isopropyl ether, dichloromethane,methyl tert-butyl ether, 2-butanone, and ethyl acetate. In someembodiments, the washing results in a purity of the compound of Formula(I) thereof greater than or equal to 99.10%, 99.20%, 99.30%, 99.40%,99.50%, 99.60%, 99.70%, 99.80%, 99.90%, 99.91%, 99.92%, 99.93%, 99.4%,99.95%, 99.96%, 99.97%, 99.98%, or 99.99%.

Some embodiments provide a kit for treating aneurysms, comprising: acompound of Formula (I) having a purity greater than or equal to 99%;and a hydrolyzer. In some embodiments, the hydrolyzer is ethanol. Insome embodiments, the hydrolyzer is dimethyl sulfoxide (DMSO). In someembodiments, the hydrolyzer is contrast media. In some embodiments, thekit further comprises a saline solution.

Some embodiments provide a device for treating an aneurysm, comprising:a shaft; a first balloon attached to a first end of the shaft; and asecond balloon attached to a second end of the shaft, the second ballooncomprising a plurality of pores for delivering a therapeutic agent tothe aneurysm. In some embodiments, the first balloon is positioned neara distal end of the shaft for anchoring the device and stoppingdownstream blood flow, and wherein the second balloon is positioned neara proximal end of the shaft. The second balloon may be configure forstopping retrograde blood flow and/or for displacing blood for theaneurysmal sac, which may improve the efficacy of drug delivery to theaneurysm. In some embodiments, the second balloon is positioned near adistal end of the shaft for anchoring the device and stopping downstreamblood flow, and wherein the first balloon is positioned near a proximalend of the shaft for stopping retrograde blood flow. In someembodiments, the device further comprises a third balloon positionedwithin the second balloon for expanding the second balloon, the thirdballoon expandable with saline.

Some embodiments provide a method for treating an aneurysm, comprising:positioning a first balloon upstream the aneurysm; positioning a secondballoon adjacent the aneurysm; inflating the first balloon to occludedownstream blood flow; expanding the second balloon to occluderetrograde blood flow and/or to displace blood from the aneurysmal sac;and delivering a therapeutic agent to the aneurysm through pores in thesecond balloon.

Some embodiments provide a method of purifying 1,2,3,4,6-pentagalloylglucose (PGG) or analogues or derivatives thereof comprising washing thePGG with a solvent to remove substantially all gallic acid or methylgallate. In some embodiments, the solvent may be or may comprise diethylether, toluene, isopropyl ether, dichloromethane, methyl tert-butylether, 2-butanone, and/or ethyl acetate. Removing substantially allgallic acid or methyl gallate may result in less than about 0.1%, 0.2%,0.3%, 0.4%, or 0.5% gallic acid or methyl gallate. The washing mayresults in a purity of the 1,2,3,4,6-pentagalloyl glucose (PGG) oranalogues or derivatives thereof greater than or equal to 99.9%.

Some embodiments provide a kit for treating aneurysms. The kit includesPGG having a purity greater than or equal to 99% and a hydrolyzer. Thehydrolyzer may be or may comprise ethanol, dimethyl sulfoxide (DMSO),and/or contrast media. The kit may include a saline solution.

Some embodiments provide a device for treating an aneurysm. The devicehas a shaft, a first balloon attached to a first end of the shaft, and asecond balloon attached to a second end of the shaft. The second balloonincludes a plurality of pores for delivering a therapeutic agent to theaneurysm. In some embodiments, the first balloon may be positioned neara distal end of the shaft for anchoring the device and stoppingdownstream blood flow, and the second balloon may be positioned near aproximal end of the shaft for stopping retrograde blood flow. In someembodiments, the second balloon may be positioned near a distal end ofthe shaft for anchoring the device and stopping downstream blood flow,and the first balloon may be positioned near a proximal end of the shaftfor stopping retrograde blood flow. The device may include a thirdballoon positioned within the second balloon for expanding the secondballoon. The third balloon may be expandable with saline.

Some embodiments provide a catheter for treating an aneurysm. Thecatheter has an elongate body configured to be introduced into a bloodvessel. The elongate body has a proximal end, a distal end, and a mainshaft having a lumen extending therethrough. The catheter has a firstinflatable balloon coupled to the distal end of the elongate body andhaving an interior volume in fluid communication with a first inflationlumen. The catheter has a second inflatable balloon coupled to theelongate body proximally to the first inflatable balloon and having aninterior volume in fluid communication with a second inflation lumen.The second inflatable balloon circumferentially surrounds the elongatebody. The second inflatable balloon has a plurality of pores disposed ona surface of the second inflatable balloon configured to place theinterior volume of the second inflatable balloon in fluid communicationwith an intravascular environment of the blood vessel.

In some embodiments, the main shaft may extend through the secondinflatable balloon. The distal end of the main shaft may form the distalend of the elongate body. The first inflation lumen and the secondinflation lumen may be formed within the main shaft. The elongate bodymay include a second shaft having a lumen extending therethrough. Thesecond shaft may be disposed within the lumen of the main shaft. Thefirst inflatable balloon may be coupled to a distal end of the secondshaft and the second inflatable balloon may be coupled to a distal endof the main shaft. The lumen of the main shaft may be the secondinflation lumen. The lumen of the second shaft may be the firstinflation lumen. The elongate body may extend through the interiorvolume of the second inflatable balloon. The second inflatable balloonmay be generally toroidal forming an annular interior volume thatsurrounds the elongate body. The elongate body may have an intermediateshaft segment positioned between a proximal end of the first inflatableballoon and a distal end of the second inflatable balloon. Theintermediate shaft segment may include the main shaft and/or the secondshaft. A separation distance between the first inflatable balloon andthe second inflatable balloon may be fixed or may be adjustable. Thecatheter may have a lumen configured to be placed in fluid communicationwith a volume of the intravascular environment between the firstinflatable balloon and the second inflatable balloon.

The pores may be disposed on a central portion of the second inflatableballoon. The pores may be disposed on a distal portion of the secondinflatable balloon. The pores may not be disposed on a proximal portionof the second inflatable balloon. The pores may not be disposed on anyportion of the second inflatable balloon proximal to a maximum expandeddiameter of the balloon in an inflated configuration. The maximumexpanded diameter of the second inflatable balloon may be greater thanthe maximum expanded diameter of the first inflatable balloon. Thelength of the expanded second inflatable balloon may be greater than thelength of the expanded first inflatable balloon.

The catheter may include a third inflatable balloon disposed within theinterior volume of the second inflatable balloon. The third inflatableballoon may have an interior volume in fluid communication with a thirdinflation lumen. Expansion of the third inflatable balloon may beconfigured to at least partially expand the second inflatable balloon.Expansion of the third inflatable balloon may be configured tofacilitate expulsion of at least a partial volume of inflation fluiddisposed within the interior volume of the second inflatable balloonthrough the pores into the intravascular environment.

Some embodiments provide a method for treating an aneurysm in a bloodvessel of a patient. The method comprises positioning a first balloonupstream the aneurysm, positioning a second balloon adjacent theaneurysm, inflating the first balloon to occlude downstream blood flow,expanding the second balloon to occlude retrograde blood flow, anddelivering a therapeutic agent to the aneurysm through pores in thesecond balloon. In some embodiments, expanding the second ballooncomprises introducing an inflation fluid into an interior volume of thesecond balloon. Delivering the therapeutic agent may compriseintroducing a solution comprising the therapeutic agent into an interiorvolume of the second balloon to expand and/or maintain an expanded stateof the second balloon. Inflating the first balloon and expanding thesecond balloon may create a sealed volume within the blood vesselbetween the first balloon and the second balloon. Delivering thetherapeutic agent may comprise introducing the therapeutic agent intothe sealed volume. The therapeutic agent may not be delivered into theblood vessel outside of the sealed volume while the sealed volume isestablished.

Inflating the first balloon may anchor the first balloon and the secondballoon within the blood vessel. Positioning the second balloon adjacentthe aneurysm may comprise positioning the second balloon across theaneurysm and expanding the second balloon may create a sealed spacebetween the second balloon and the aneurysm. Positioning the secondballoon adjacent the aneurysm may comprise positioning the secondballoon along a downstream edge of the aneurysm and expanding the secondballoon may create a sealed volume between the first balloon and thesecond balloon which encompasses the aneurysm. Positioning the secondballoon adjacent the aneurysm may comprise positioning the secondballoon such that a length of the aneurysm along the blood vesselencompasses an entire length of the second balloon. Inflating the firstballoon may occur prior to expanding the second balloon. Expanding thesecond balloon and/or maintaining the second balloon in an expandedstate may comprise maintaining a pressure within an interior volume ofthe second balloon greater than a diastolic blood pressure of thepatient and less than a systolic blood pressure of the patient.Expanding the second balloon and delivering the therapeutic agentthrough the pores may comprise introducing a solution into an interiorvolume of the second balloon. The solution may be introduced at a firstvolumetric flow rate to expand the second balloon and at a secondvolumetric flow rate to deliver the therapeutic agent through the pores.The first volumetric flow rate may be greater than or equal to thesecond volumetric flow rate.

Blood flow may be occluded within the blood vessel for no longer thanapproximately 3 minutes. At least 1 mL of solution comprising thetherapeutic agent may be delivered while downstream blood flow andretrograde blood flow vessel is occluded. Expanding the second balloonmay comprise inflating a third balloon disposed within an interiorvolume of the second balloon. Delivering the therapeutic agent maycomprise inflating a third balloon disposed within an interior volume ofthe second balloon to force a volume of solution comprising thetherapeutic agent within the interior volume of the second balloonthrough the pores. The therapeutic agent may comprise pentagalloylglucose (PGG). The PGG may be at least 99.9% pure. The therapeutic agentmay be substantially free of gallic acid or methyl gallate.

BRIEF DESCRIPTION OF THE DRAWINGS

The features and advantages of the systems, devices, and methodsdescribed herein will become apparent from the following description,taken in conjunction with the accompanying drawings. These drawingsdepict only several embodiments in accordance with the disclosure andare not to be considered limiting of its scope. In the drawings, similarreference numbers or symbols typically identify similar components,unless context dictates otherwise. The drawings may not be drawn toscale.

FIG. 1A depicts the chemical structure of 1,2,3,4,6-pentagalloyl glucose(PGG) in a preferred embodiment.

FIG. 1B depicts the chemical structure of gallic acid, a common toxicimpurity in the production of PGG.

FIG. 1C depicts the chemical structure of methyl gallate, a common toxicimpurity in the production of PGG.

FIGS. 2A-2C schematically depict various examples of a delivery catheterfor the delivery of PGG or another therapeutic agent to a blood vessel.FIG. 2A depicts a delivery catheter in which the downstream balloon iscoupled at a proximal end to the distal end of the main shaft and at thedistal end to the secondary shaft, and in which the upstream balloon iscoupled to the distal end of the secondary shaft. FIG. 2B depicts adelivery catheter in which the downstream balloon is a generallytoroidal balloon coupled to the distal end of the main shaft andsurround the secondary shaft, and in which the upstream balloon iscoupled at proximal and distal ends to the secondary shaft. FIG. 2B alsoillustrates a supplemental internal lumen in fluid communication with asealed volume created between the upstream balloon and the downstreamballoon and a lead segment positioned on a distal end of the deliverycatheter. FIG. 2C depicts a delivery catheter in which the downstreamballoon is coupled at proximal and distal ends to the main shaft, and inwhich the upstream balloon is coupled at proximal and distal ends to thesecondary shaft. FIG. 2C also illustrates a secondary shaft having acentral lumen which is open at the distal end of the delivery catheterand in fluid communication with the intravascular environment.

FIGS. 3A-3C schematically depict various examples of a downstreamballoon of a delivery catheter expanded within a blood vessel comprisingan aneurysm. FIG. 3A depicts a downstream balloon that is longer inlength than the aneurysm and which is expanded to create a sealed spacebetween the downstream balloon and the blood vessel wall of theaneurysm. FIG. 3A also depicts pores being disposed on a central portionof the downstream balloon. FIG. 3B schematically depicts a downstreamballoon expanded to fluidly seal a downstream edge of the aneurysm,creating a sealed volume between the downstream balloon and the upstreamballoon. FIG. 3B also depicts pores being disposed on a distal portionof the downstream balloon. FIG. 3C depicts a downstream balloon that isshorter in length than the aneurysm and which is expanded to bring thedownstream balloon into contact with the blood vessel wall of theaneurysm.

FIGS. 4A-4C schematically depict various examples of a delivery cathetercomprising an inner balloon disposed within the downstream balloon. FIG.4A depicts the inner balloon coupled at a proximal end to the distal endof the main shaft and coupled at a distal end to the secondary shaft.FIG. 4B depicts the inner balloon coupled at proximal and distal ends tothe secondary shaft. FIG. 4C depicts the inner balloon coupled atproximal and distal ends to the main shaft.

DETAILED DESCRIPTION

Disclosed herein are methods of purifying and delivering pentagalloylglucose (PGG). In preferred embodiments, the PGG may be1,2,3,4,6-pentagalloyl glucose as depicted in FIG. 1A. However, PGG mayrefer to any chemical structure encompassed by Formula (I), disclosedelsewhere herein. Further disclosed herein, are devices for delivery ofPGG or another therapeutic agent to a blood vessel or other body lumen,although the treatment with PGG disclosed herein is not necessarilylimited to delivery with these devices. Additionally, the devicesdisclosed herein may be used to delivery any suitable therapeutic agentto any suitable site of a subject. PGG may be delivered to a subject totreat any one or more of various indications.

In a preferred embodiment, PGG may be delivered to the blood vessel wallfor treatment of an aneurysm, such as an abdominal aortic aneurysm.Without being limited by theory, the delivery of PGG to the blood vesselwall where an aneurysm has formed may stabilize the aneurysm bycross-linking, at least transiently, the elastin proteins within theextracellular matrix of the connective tissue of the blood vessel wall.Treatment of the blood vessel with an elastin-stabilizing compound, suchas PGG, may increase the mechanical integrity of the blood vessel wherethe aneurysm is present. Treatment with PGG may prevent, inhibit, and/orslow the growth of an aneurysm and further thinning of the blood vesselwall and may prevent, inhibit, reduce the likelihood of, and/or delaythe risk of rupture of the aneurysm. In some instances, treatment withPGG may facilitate natural healing of the aneurysm by mechanicallystabilizing the aneurysm. In some implementations, treatment with PGGmay be used prior to, after, and/or concurrently with otherinterventional treatment of an aneurysm, such as surgical intervention.In some implementations treatment of PGG may be particularly suitablefor treating abdominal aortic aneurysms between approximately 4-5 cm indiameter. Treatment of an abdominal aortic aneurysm may, in some cases,delay the need for more traditional invasive therapies by at least about10 years.

In other applications, PGG may be used to treat aneurysms besidesabdominal aortic aneurysms, including peripheral and neural aneurysms.PGG may be delivered to these aneurysms by the same device as describedherein with respect to abdominal aortic aneurysms or one similar theretoor may be delivered using another device or route of administration. Forinstance, in some embodiments, PGG, particularly a high purity PGG asdisclosed herein, may be suitable for direct injection into thebloodstream or into another tissue for treatment of other indications.In some embodiments, PGG may be used to stabilize and/or facilitateclosure of vascular access holes created by puncturing a blood vessel toaccess the blood stream for drawing blood and/or for therapeutictreatment via the vasculature, such as delivery of a catheter. PGG maypromote closure of the vascular access site by means to those fortreating an aneurysm. The PGG may stabilize the blood vessel wall aroundthe access hole by crosslinking elastin within the blood vessel, whichmay promote or accelerate natural healing. PGG may be applied to theaccess hole via intravascular application and/or by applying PGGdirectly to the skin over the vascular access hole. PGG may havebeneficial effects toward wound closure in connective tissue comprisingelastin outside the blood vessel wall, such as the superficial layers ofskin above the vascular access hole, including subcutaneous tissue.Similarly, PGG may be used to treat musculoskeletal conditions,including the treatment of injured ligaments and/or tendons, bycrosslinking the elastin within the connective tissue. PGG may be usedto coat vascular stents and/or grafts. PGG delivered to blood vesselwalls after angioplasty, for instance, may structurally stabilize theblood vessel wall and help prevent or inhibit restenosis of the bloodvessel. Additionally, PGG may be used to treat and/or prevent aorticdissection. Treatment of an aortic dissection with PGG may help close atear in the media layer of the blood vessel, may prevent propagation ofthe tear along the blood vessel wall, and/or may stabilize the tearpromoting natural healing. In some instances, PGG may be delivered to anaortic dissection using the delivery device described herein or onesimilar thereto.

Purified PGG

The concentrations of PGG which may be safely delivered to a patient maybe generally proportional to the purity of the PGG. For example, gallicacid, depicted in FIG. 1B, and methyl gallate, depicted in FIG. 1C, arecommon cytotoxic impurities which may be removed from a source batch ofPGG during the purification process. Eliminating the presence of orreducing the concentration of toxic impurities from the delivered PGGmay allow higher concentrations of the PGG to be delivered due to themitigation of the toxic side effects of impurities commonly found inisolated PGG. For instance, studies have shown that substantially 100%pure PGG may be safely delivered at concentrations up to approximately0.330% (w/v), 95% pure PGG may be safely delivered at concentrations upto approximately 0.125% (w/v), and 85% pure PGG may be safely deliveredat concentrations up to approximately 0.06% (w/v). Delivery of PGG inhigher concentrations may enhance the amount of uptake of PGG by thetarget tissue which may increase the efficacy of the PGG treatment.Delivery of PGG in higher concentrations may increase the rate of uptakeof PGG by the tissue allowing the same amount of uptake in shorterdelivery times. Reducing or minimizing the delivery time may beadvantageous for reducing the overall treatment time, and particularlythe duration of time for which a blood vessel, such as the aorta, ispotentially occluded, as described elsewhere herein. Minimization of thetreatment time and particularly the duration of blood occlusion mayimprove the safety and convenience of the treatment procedure andimprove patient outcomes.

Unpurified or partially purified PGG may be obtained from any suitablesource and purified according to the methods described herein for use asa therapeutic agent. PGG may be extracted from naturally occurringplants such as pomegranate or Chinese gall nut. Extraction and/orisolation methods may entail solvolysis (for example, methanolysis) oftannin or derivative polyphenols as is known in the art. A PGG hydrateis commercially available from Sigma Aldrich (St. Louis, Missouri) atpurities greater than or equal to 96%, as confirmed by HPLC. PGGobtained from these sources may undergo additional purificationaccording to the methods described herein to arrive at substantiallypure PGG at the purity levels described elsewhere herein.

In some embodiments, PGG is purified by washing a starting batch of PGG(e.g, less than 99% pure) with a solvent. In preferred embodiments, thesolvent may comprise diethyl ether. In other embodiments, the solventmay comprise methanol, toluene, isopropyl ether, dichloromethane, methyltert-butyl ether, 2-butanone, and/or ethyl acetate. In some embodiments,the washing solution may comprise mixtures of the solvents describedherein and/or may be mixed with additional solvents. In someembodiments, the starting batch of PGG may be dissolved into a solution.In some embodiments, the PGG may be dissolved in dimethyl sulfoxide(DMSO). In some embodiments, the PGG may be dissolved in any solvent inwhich the PGG is soluble and which is not miscible with the washingsolution. The PGG solution may be mixed with the washing solution in aflask and the PGG solution and washing solution may be allowed toseparate over time. The washing solution may subsequently be separatedfrom the PGG solution, such as by draining the denser solution from theflask or by decanting the less dense solution. In some embodiments, themixture of the washing solution and PGG solution may comprise avolume-to-volume ratio of at least about 1:1, 1.5:1, 2:1, 3:1, 4:1, 5:1,or 10:1 washing solution-to-PGG solution. In some embodiments, thewashing step may be repeated at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10times. In some embodiments, the washed PGG solution may be evaporatedupon purification to precipitate the PGG into a dry (solid) form. Insome embodiments, the PGG may remain dissolved, but the volume of thesolution may be increased or decreased (for example, by evaporation). Insome embodiments, the starting batch of PGG may be in a dry (solid)form. The PGG may be crystalized. In some embodiments, the PGG may belyophilized. In some embodiments, the PGG may be precipitated fromsolution. In some embodiments, the starting batch of PGG may be placedon filter paper and the washing solution poured over the filter paperinto a waste flask. The filtration may be facilitated by application ofa vacuum to the waste flask (vacuum filtration). Residual washingsolution may be evaporated from the purified batch of PGG. In someembodiments, the washing step may be repeated at least 1, 2, 3, 4, 5, 6,7, 8, 9, or 10 times. The purity of the PGG may increase with each wash.The washing procedure may be repeated until a desired level of purity isattained.

In some embodiments, washing the PGG may result in a purity of at leastapproximately 99.000%, 99.500%, 99.900%, 99.950%, 99.990%, 99.995%, or99.999% purity. Purity may be measured as the percent mass (w/w) of PGGin a sample. Purity of the PGG may be measured by any standard meansknown in the art including chromatography and nuclear magnetic resonance(NMR) spectroscopy. In some embodiments, the purified PGG may compriseno more than approximately 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%,0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% gallic acid. In someembodiments, the purified PGG may comprise no more than approximately0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%,0.8%, 0.9%, or 1% methyl gallate.

Kits for Delivery of PGG

PGG may be prepared in a solution for delivery as a therapeutic agent toa patient. The PGG may comprise a purity described elsewhere herein. ThePGG may have been purified by the methods disclosed elsewhere herein ormay have been purified by other means. In some embodiments, the PGG maybe dissolved in a hydrolyzer for subsequent delivery to a patient. Thehydrolyzer may comprise any solvent or mixture of solvents in which PGGis readily soluble and which is miscible with water. In someembodiments, the hydrolyzer may be ethanol. In some embodiments, thehydrolyzer may be dimethyl sulfoxide (DMSO). In some embodiments, thehydrolyzer may be contrast media. In some embodiments, the hydrolyzermay be a mixture of ethanol, DMSO, and/or contrast media in anyproportions. The hydrolyzer may facilitate the dissolution of PGG into alarger aqueous solution, in which the PGG would not normally be solubleat the same concentration without first being dissolved into thehydrolyzer. The PGG may ultimately be dissolved into a non-toxic aqueoussolution suitable for delivery, such as intravascular delivery, to apatient. The aqueous solution may be a saline solution, as is known inthe art, or another aqueous solution comprising salts configured tomaintain physiological equilibrium with the intravascular environment.The volumetric ratio of the hydrolyzer to the saline solution may beminimized, while maintaining a sufficient volume of hydrolyzer to fullydissolve the desired amount of PGG, to minimize any harmful or toxiceffects of the hydrolyzer on the patient, particularly when deliveredintravascularly. In some embodiments, the volume-to-volume ratio ofsaline to hydrolyzer may be no less than about 10:1, 25:1, 50:1, 75:1,100:1, 200:1, 300:1, 400:1, 500:1, 600:1, 700:1, 800:1, 900:1, or1000:1. The total volume of the hydrolyzer and saline mixture (includingany other additional components) may be configured to prepare the PGG toa desired therapeutic concentration, such as the concentrationsdescribed elsewhere herein. In some embodiments, the PGG may bedissolved into the saline or other aqueous solution without ahydrolyzer. In some embodiments, the saline may be warmed (e.g., toabove room temperature or above physiological temperature) to dissolveor help dissolve the PGG (or other therapeutic agent). For instance, thesaline may be warmed to at least about 25° C., 30° C., 35° C., 40° C.,45° C., 50° C., 55° C., or 60° C. prior to dissolving the PGG. In someimplementations, the therapeutic solution may be raised to and/ormaintained at an elevated temperature (e.g., physiological temperature)during delivery.

In some embodiments, PGG (for example, purified PGG) for a therapeutictreatment, including but not limited to those described elsewhereherein, may be provided in a kit comprising the components necessary toprepare the PGG for delivery in a therapeutic solution. In someembodiments, the kit may comprise the PGG in a solid (dry) form, thehydrolyzer, and/or the saline solution. The kit may be configured tooptimize the storage conditions of the PGG, for short or long-termstorage. In some embodiments, the kit may be configured to store the PGGfor up to at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months,3 months, 4 months, 5 months, 6 months, 1 year, 2 years, or 3 years. Thekit may comprise one or more aliquots of each component in pre-measuredamounts or volumes. Each component may be provided in a sealed vial,tube, or other container as is known in the art. The containers may eachcomprise plastic and/or glass. The containers may be configured (forexample, tinted or covered) to protect the components from light and/orother radiation. In some embodiments, the kit may be configured forshipping. For example, the components may be contained in a box or othercontainer including desiccants and/or may be configured for temperaturecontrol. In some embodiments, the PGG and/or other components may besupplied in a container that has been purged of air (particularly,oxygen). The component may be stored under vacuum or may be purged withan inert gas, such as nitrogen or argon. In some embodiments, the PGGmay be mixed with an antioxidant or other stabilizer, in addition to oralternatively to purging the air. In some embodiments, the antioxidantmay comprise Vitamin C, Vitamin E, and/or any other antioxidant orstabilizer which is known in the art and is safe for treatment. In someembodiments, the PGG may be provided already dissolved in the hydrolyzerto a predetermined concentration. In some embodiments, the volume ofsaline provided may be configured to prepare the PGG at a desiredtherapeutic concentration. In some embodiments, the volume of saline maybe configured to prepare the PGG at a maximal therapeutic concentration,such that a user may dilute the PGG with additional solvent to thedesired therapeutic concentration. In some embodiments, the total volumeof saline may be configured to prepare the PGG at a concentration belowthe desired concentration and the user may use only a portion of thevolume of the saline to prepare the PGG to the desired concentration.The container of saline may have volume indicators for facilitatingmeasurement of the saline. In some embodiments, the saline may beprovided in a plurality of aliquots having the same and/or differentvolumes, which may allow the user to select an aliquot of a desiredvolume to prepare the PGG at a desired concentration and/or combinevarious volumes to prepare the

PGG at a desired concentration. In some embodiments, the kit maycomprise one or more additional components. For example, the kit maycomprise a contrast agent for mixing with the therapeutic PGG solutionfor allowing indirect visualization of the therapeutic solution, asdescribed elsewhere herein.

Delivery Devices

In some implementations, PGG and/or other therapeutic agents ormedicaments, including but not limited to those described elsewhereherein, may be delivered to the site of an aneurysm, such as anabdominal aortic aneurysm, or to an isolated section of a blood vesselvia a catheter device as described herein. Abdominal aortic aneurysmsare generally found in the abdominal aorta downstream of the renalarteries, above where the aorta splits into the iliac arteries. Thedelivery catheter may be specifically configured (for example,dimensioned), for delivery of a therapeutic agent to an abdominal aorticaneurysm.

FIG. 2A schematically depicts an example of a delivery catheter 100. Thedelivery catheter 100 may comprise a proximal end (not shown),configured to remain outside of the body during use, and a distal end102, configured to be positioned within the blood vessel near (generallydistal to) the target aneurysm or target site or section of blood vesselto be treated. The delivery catheter 100 may comprise a main shaft 110,an upstream expandable member 104 and a downstream expandable member106. The delivery catheter 100 may have a longitudinal axis extendingfrom the downstream expandable member 106 to the upstream expandablemember 104. The upstream expandable member 104 may be positioned at ornear the distal end 102 of the delivery catheter 100 and the downstreamexpandable member 106 may be positioned proximally to the upstreamexpandable member 104. Such a configuration is useful for introductionof the delivery catheter 100 from a vascular access point downstream ofthe target aneurysm or blood vessel location. For instance, such aconfiguration is useful for introduction of the delivery catheter 100through the femoral artery to treat an abdominal aortic aneurysm. Inalternative embodiments, the delivery catheter 100 may be configured forintroduction from a location upstream the target aneurysm or target siteof the blood vessel and the upstream expandable member 104 may bepositioned proximally to the downstream expandable member 102 withrespect to the delivery catheter.

Each expandable member 104, 106 may comprise an expanded configurationhaving an expanded radial diameter and an unexpanded configurationhaving an unexpanded radial diameter, the expanded radial diameter beinglarger than the unexpanded radial diameter. The length of one or both ofthe expandable members 104, 106 may increase, decrease, or remain thesame upon expansion. The unexpanded diameter of each expandable member104, 106 may be configured to facilitate insertion of the deliverycatheter 100 into the blood vessel. The unexpanded diameters may each beless than, approximately the same as, or larger than an inner diameterand/or outer diameter of the main shaft 110. The expanded diameter ofeach expandable member 104, 106 may be configured to occlude the targetblood vessel and may be the same as or larger than the diameter of thetarget blood vessel (for example, the abdominal aorta). In someembodiments, one or both of the expandable members 104, 106 may beoperable at intermediate diameters between the unexpanded and fullyexpanded diameter. The unexpanded diameter of the upstream expandablemember 104 may be the same as or different from the unexpanded diameterof the downstream expandable member 106. Similarly, the expandeddiameter of the upstream expandable member 104 may be the same as ordifferent from the expanded diameter of the downstream expandable member106.

In various embodiments, the upstream expandable member 104 may be aninflatable balloon 105 as shown in FIG. 2A. In various embodiments, thedownstream expandable member 106 may be an inflatable balloon 107, alsoshown in FIG. 2A. The inflatable balloons 105, 107 may comprise anelastic material forming an expandable membrane as is known in the artand may be configured to expand upon pressurization from an inflationfluid (for example, a gas or a liquid, such as saline). The balloonmaterial may be biocompatible. In some embodiments, the upstreamexpandable member 104 and/or the downstream expandable member 106 may beexpandable through means other than or in addition to inflation. Forexample, one or both of the expandable members 104, 106 may compriseradially expandable frames. The expandable frames may comprise a shapememory material (for example, a nickel titanium alloy (nitinol)) and/ormay be configured to self-expand. One or both of the expandable members104, 106 may be configured to self-expand upon release of a constrainingmechanism, such as an outer sheath surrounding the expandable member,which may, for instance, be proximally withdrawn to allow self-expansionof the expandable member. In some embodiments, one or both of theexpandable frames may be configured to be mechanically expanded, such asby a push wire or pull wire extending through an internal lumen of thedelivery catheter 100. The expandable frames may be fixed or coupled toa surrounding fluid impermeable covering or coating such that theexpandable members 104, 106 may be configured to occlude fluid flow asdescribed elsewhere herein.

The main shaft 110 of the delivery catheter 100 may extend from theproximal end of the delivery catheter 100 to the downstream balloon 107(or other downstream expandable member 106). The main shaft 110 maycomprise a length and a diameter configured to facilitate navigation ofthe distal end 102 of the delivery catheter 100 to the target site,which may depend on the particular application and/or vascular accesssite. In some embodiments, the diameter may vary over a length of themain shaft 110 and/or any internal components, including internal shaftsdescribed elsewhere herein. For example, the diameter may decrease in aproximal to distal direction causing a distal portion of the deliverycatheter 100 to be more flexible than a proximal portion. As shown inFIG. 2A, the downstream balloon 107 may be attached to a distal end ofthe main shaft 110. The main shaft 110 may have a first central lumen112. The main shaft 110 may be generally tubular having a sidewallforming the first inflation lumen central lumen 112. The first centrallumen 112 may serve as a first inflation lumen 113 for inflating and/ordeflating the downstream balloon 107. The first inflation lumen 113 maybe in fluid communication with an interior volume of the downstreamballoon 107. An inflation fluid (for example, saline) may be introducedfrom a proximal end of the delivery catheter 100 through the firstinflation lumen 113 into the interior volume of the downstream balloon107 for inflating or expanding the balloon 107 and removed (for example,aspirated from the balloon 107) through the first inflation lumen 113 tode-inflate the balloon 107. The proximal end of the first inflationlumen 113 and/or any other inflation lumens described herein may each bein fluid communication with a source of pressurized inflation fluid,such as a syringe, an IV bag, a fluid pump, etc. One or more of theinflation lumens and/or balloons described herein may be in fluidcommunication with one or more pressure sensors for monitoring pressurelevels within the internal lumens and/or the balloons with which theyare in fluid communication. In some embodiments in which the downstreamexpandable member 106 comprises an expandable frame, a pull wire or pushwire may extend through the first inflation lumen 113 for actuating theexpansion or compression of the downstream expandable member 106.

A secondary shaft 114 may extend from a proximal end of the deliverycatheter 100 to the upstream balloon 105 (or other upstream expandablemember 104). As shown in FIG. 2A, the upstream balloon 105 may beattached to a distal end of the secondary shaft 114. In someembodiments, the secondary shaft 114 may extend through the firstcentral lumen 112. The secondary shaft 114 may comprise a secondarycentral lumen 116. The secondary shaft 116 may be generally tubularhaving a sidewall forming the secondary central lumen 116. The secondcentral lumen 116 may serve as a second inflation lumen 117 forinflating and/or deflating the upstream balloon 105. The secondaryinflation lumen 116 may be in fluid communication with an interior ofthe upstream balloon 105. An inflation fluid (for example, saline) maybe introduced from a proximal end of the delivery catheter 100 throughthe secondary inflation lumen 117 into the interior volume of theupstream balloon 105 for inflating or expanding the balloon 105 andremoved (for example, aspirated from the upstream balloon 105) throughthe secondary inflation lumen 117 to de-inflate the upstream balloon105. In some embodiments in which the upstream expandable member 104comprises an expandable frame, a pull wire or push wire may extendthrough the secondary inflation lumen 117 for actuating the expansion orcompression of the upstream expandable member 104.

In some embodiments, as shown in FIG. 2A, the secondary shaft 114 mayextend through the first central lumen 112. In some embodiments, thesecondary shaft 114 may be freely disposed within the first centrallumen 112 in a substantially concentric manner. In some embodiments, thesecondary shaft 114 may be substantially coaxial with respect to thefirst central lumen 112. A substantially annular lumen may be formedbetween the inner diameter of the sidewall of the main shaft 110 and theouter diameter of the sidewall of the secondary shaft 114.Alternatively, the secondary shaft 114 may be coupled to or formedintegrally with the inner diameter of the sidewall of the main shaft110. The distal end of the secondary shaft 114 may extend or beconfigured to be extendable distally beyond the distal end of the mainshaft 110. The secondary shaft 114 may extend through a central portionof the downstream balloon 107 (or other downstream expandable member105).

In some embodiments, as depicted in FIG. 2A, the secondary shaft 114 mayextend through the interior of the downstream balloon 107. Thedownstream balloon 107 may comprise an expandable membrane having aproximal end and a distal end. The proximal end of the expandablemembrane may be coupled to (for example, at or near) the distal end ofthe main shaft 110. The distal end of the expandable membrane may becoupled to the secondary shaft 114 at a point proximal to the upstreamballoon 105. The proximal and distal ends of the expandable membrane maybe coupled to main shaft 110 and the secondary shaft 114 to formfluid-tight seals around the outer diameters of the shafts 110, 114,allowing inflation fluid to pressurize the interior volume of thedownstream balloon 107 and the expandable membrane to expand radiallyoutward between the proximal and distal ends of the expandable membraneupon the introduction of the inflation fluid.

In some embodiments, the downstream balloon 107 may have a generallytoroidal configuration, as schematically illustrated in FIG. 2B, inwhich the expandable membrane of the downstream balloon 107 has an outersurface and an inner surface, the inner surface forming a closedcircumference defining a central hole through which the secondary shaft114 may extend. The downstream balloon 107 may define an annularinterior volume configured to be pressurized by introduction ofinflation fluid from the first inflation lumen 113. In some embodiments,the downstream balloon 107 may be coupled to the distal end of the mainshaft 110 such that it is in fluid communication with the annular shapedlumen 112 as described with respect to FIG. 2A. In some embodiments, thedownstream balloon 107 may be coupled to an outer circumference of themain shaft 110 and in fluid communication with an inflation port formedin the sidewall of the main shaft 110, as described elsewhere herein. Insome embodiments, the generally toroidal downstream balloon 107 maycomprise a distal coupling, such as a coupling ring 111, configured tocouple a distal end of the downstream balloon 107 to the main shaft 110,the secondary shaft 114, or another component of the delivery catheter100. The distal coupling may orient the downstream balloon 107 in aproper configuration with respect to the delivery catheter 100. Thedistal coupling may rigidly fix the downstream balloon 107 to thecoupled component (for example, secondary shaft 114) or it may allow thecoupled component to axially translate along the longitudinal axis withrespect to the distal end of the downstream balloon 107, as describedelsewhere herein. In some embodiments, the inner surface of theexpandable membrane of the downstream balloon 107 may be coupled to (forexample, adhered via an adhesive) an outer diameter of the main shaft110, the secondary shaft 114, and/or another component of the deliverycatheter 100.

In other embodiments, as depicted in FIG. 2C, the main shaft 110 mayextend distally to or beyond the distal end of the expandable membraneof the downstream balloon 107. In such embodiments, both the proximaland distal ends of the expandable membrane may be coupled to the mainshaft 110. The first inflation lumen 113 may be formed within thesidewall of the main shaft 110 and may be sealed at the distal end toprevent the escape of the inflation fluid. The first inflation lumen 113may be formed separately from the first central lumen 112. The firstinflation lumen 113 may be positioned radially outside of the firstcentral lumen 112. The first central lumen 112 may be configured toreceive the secondary shaft 114, as described with respect to FIG. 2A.The main shaft 110 may have one or more inflation ports 118 in fluidcommunication with the interior volume of the downstream balloon 107 andthe first inflation lumen 113. The inflation ports 118 may pass througha sidewall of the main shaft 110. In some embodiments, a plurality ofinflation ports 118 may be spaced longitudinally along the main shaft110 between the proximal and distal ends of the expandable membrane. Insome embodiments, a plurality of inflation ports 118 may be spacedradially around the outer diameter of the main shaft 110. The distal endof the main shaft 110 may be positioned at or just beyond the distal endof the downstream balloon 107, as shown in FIG. 2C. In some embodiments,the main shaft 110 may extend to the upstream balloon 105. In someembodiments, the first central lumen 112 may be in fluid communicationwith a sealed volume 142, described elsewhere herein, formed between theupstream balloon 105 and the downstream balloon 107. In someimplementations, the first central lumen 112 may be used to deliver atherapeutic agent into the sealed volume 142 and/or to aspirate fluidfrom the sealed volume 142, as described elsewhere herein.

The delivery catheter 100 comprises an intermediate shaft segment 120extending between the downstream balloon 107 and the upstream balloon105 (or between other expandable members 104, 106) and configured tospace the upstream balloon 105 distally from the downstream balloon 107.The intermediate shaft segment 120 may connect the upstream balloon 105and downstream balloon 107. In some embodiments, such as that describedwith respect to FIG. 2A, the secondary shaft 114 may form theintermediate shaft segment 120 (or at least an outer component of theintermediate shaft segment 120). In some embodiments, the main shaft 110may form the intermediate shaft segment 120 (or at least an outercomponent of the intermediate shaft segment 120) or at least a portionof the length of the intermediate shaft segment 120. In someembodiments, a separate tubular connector (not shown) extending from adistal end of the downstream balloon 107 to a proximal end of theupstream balloon 105 may form the outermost component of theintermediate shaft segment 120 and the main shaft 110 and/or secondaryshaft 114 may pass through the tubular connector.

The upstream balloon 105 may comprise an expandable membrane. Theexpandable membrane of the upstream balloon 105 may comprise the sameand/or different material(s) as the expandable membrane of thedownstream balloon 107. In some embodiments, such as that shown in FIG.2A, a proximal end of the expandable membrane may be coupled to (forexample, at or near) the distal end of the secondary shaft 114 forming afluid tight seal with the secondary shaft 114. The expandable membranemay not be further coupled to any portion of the delivery catheter 100distal to the proximal seal, as shown in FIG. 2A, and the upstreamballoon 105 may form the distal-most part of the delivery catheter 100.Introduction of inflation fluid into the interior volume of the upstreamballoon 105 may cause the upstream balloon 105 to expand radially anddistally. In some embodiments, a proximal end of the upstream balloon105 may be coupled to a shaft positioned concentrically around thesecondary shaft 114, such as the main shaft 110 or a separate tubularconnector as described elsewhere herein, rather than to the secondaryshaft 114 itself. The main shaft 110 or other component to which theupstream balloon 105 is coupled may be fluidly sealed (for example,between an inner diameter of the main shaft 110 and the outer diameterof the secondary shaft 114) such that inflation fluid introduced into aninterior volume of the upstream balloon 105 through the secondaryinflation lumen 117 may ed to pressurize the upstream balloon 105.

In some embodiments, such as depicted in FIG. 2C, the expandablemembrane of the upstream balloon 105 may form a proximal seal and adistal seal with a shaft or shafts of the delivery catheter 100, similarto the downstream balloon 107 as depicted in FIG. 2C. The proximal endof the expandable membrane may be coupled to a proximal point on thesecondary shaft 114 and the distal end of the expandable membrane may becoupled to (for example, at or near) the distal end of the secondaryshaft 114 at a point distal to the proximal point. The proximal anddistal ends of the expandable membrane may be coupled to the secondaryshaft 114 to form fluid-tight seals around the outer diameter of theshaft 114, allowing inflation fluid to pressurize the interior volume ofthe upstream balloon 105 and the expandable membrane to expand radiallyoutward between the proximal and distal ends of the expandable membraneupon the introduction of the inflation fluid. The second inflation lumen117 may be formed separately from the second central lumen 116, asdepicted in FIG. 2C. The second inflation lumen 117 may be positionedradially outside of the second central lumen 116. The second centrallumen 116 may be configured to receive additional components such asguidewires, as described elsewhere herein. In other embodiments, asshown in FIG. 2B, the secondary shaft 114 may be sealed at or near itsdistal end and the second central lumen 116 may serve as the secondaryinflation lumen 117. The secondary shaft 114 may have one or moresecondary inflation ports 122 in fluid communication with the interiorvolume of the upstream balloon 105 and the secondary inflation lumen117. The secondary inflation ports 122 may pass through a sidewall ofthe secondary shaft 114. In some embodiments, a plurality of secondaryinflation ports 122 may be spaced longitudinally along the secondaryshaft 114 between the proximal and distal ends of the expandablemembrane. In some embodiments, a plurality of secondary inflation ports122 may be spaced radially around the outer diameter of the secondaryshaft 114. The distal end of the secondary shaft 114 may be positionedat or just beyond the distal end of the upstream balloon 105, as shownin FIG. 2C. In some embodiments, as described elsewhere herein, anadditional shaft and/or lumen may extend through the second centrallumen 116 of the secondary shaft 114 and may extend distally beyond thesecondary shaft 114.

In some embodiments, a lead segment 124, such as a rod, may bepositioned at a distal end of the delivery catheter 100, asschematically depicted in FIG. 2B. The lead segment 124 may be coupledto or formed from a distal end of the secondary shaft 114 and/or adistal end of the upstream balloon 105. The lead segment 124 maycomprise an atraumatic (for example, rounded) distal tip. The leadsegment 124 may facilitate the introduction and navigation of thedelivery catheter 100 within the vasculature. In some embodiments, thelead segment 124, may comprise a radiopaque material.

In various embodiments, the delivery catheter may combine or interchangethe various features illustrated and/or described with respect to FIGS.2A-2C. For instance, the configurations of the upstream balloon 105and/or the downstream balloon 107 in each example may be exchanged.

In some embodiments, the upstream balloon 105 may be configured toanchor the delivery catheter 100 within the vasculature when in anexpanded configuration, which may include full or partial expansion.Anchoring the delivery catheter 100 within the vasculature may stablyposition the downstream balloon 107 and/or other portions of thedelivery catheter 100 at an appropriate position within the vasculatureadjacent an aneurysm or other target site. The upstream balloon 105 maybe configured to occlude blood flow (for example, downstream orantegrade blood flow), at least within a sealed volume between theupstream balloon 105 and downstream balloon 107, when in an expandedconfiguration. The expandable membrane of the upstream balloon 105 maybe sufficiently compliant or conformable to assume the shape of andocclude the target vasculature. In some embodiments, the upstreamballoon 105 may be configured to occlude the abdominal aorta.

In some embodiments, the downstream balloon 107 may be configured toocclude blood flow (for example, upstream or retrograde blood flow) whenin an expanded configuration. In some embodiments, the downstreamballoon 107 may be configured to displace blood from the aneurysmal sacof an aneurysm. For example, in some implementations, the downstreamballoon 107 may be aligned with an aneurysm (e.g., the length of theaneurysm may encompass the length of the downstream balloon 107) andinflating or expanding the downstream balloon 107 may displace bloodfrom the volume of the aneurysmal sac. Displacing blood from theaneurysmal sac may improve the efficacy of delivering therapeutic agentto an aneurysm (e.g., through the downstream balloon 107). For instance,the therapeutic agent will not be diluted or will be less diluted byblood within the aneurysmal sac. The expandable membrane of thedownstream balloon 107 may be sufficiently compliant or conformable toassume the shape of and occlude the target vasculature. In someembodiments, the downstream balloon 107 may be non-compliant (forexample, a bag member having an membrane enclosing an expandableinterior volume) or less compliant than the upstream balloon 105. Insome embodiments, the downstream balloon 107 may be equally compliantrelative to the upstream balloon 105. In some embodiments, thedownstream balloon 107 may be configured to occlude the abdominal aorta.In some implementations, the downstream balloon 107 may require a lowerthreshold pressure to occlude, or fluidly seal, retrograde blood flow ifantegrade blood flow has already been stopped. For example, the upstreamballoon 105 may require an inflation pressure greater than or equal tothe systolic blood pressure to maintain its expanded configuration andthe downstream balloon 107 may require a pressure greater than or equalto the diastolic pressure to maintain its expanded configuration. Insome implementations, the role of the downstream balloon 107 and theupstream balloon 105 may be reversed, such as if the delivery catheter100 is introduced from an upstream location.

In some embodiments, the downstream balloon 107 may be configured todeliver a therapeutic agent, such as a PGG solution, to an aneurysm orother target vasculature site. The downstream balloon 107 may be what isknown in the art as a weeping balloon. The downstream balloon 107 maycomprise a plurality of pores 126 disposed in the expandable membrane ofthe balloon configured to place the interior volume of the downstreamballoon 107 in fluid communication with the intravascular environment.The solution of therapeutic agent may be used as the inflation fluid.The pores 126 may be configured to provide fluid communication betweenthe interior volume of the downstream balloon 107 and the intravascularenvironment while allowing for pressurization and inflation of thedownstream balloon 107. In some embodiments, the size of the pores 126may increase as the expandable membrane of the downstream balloonexpands. The elastic properties of the expandable membrane of thedownstream balloon 107 may allow for a continuous expansion of the poresize of the pores 126 as the interior volume of the downstream balloon107 is increased causing the expandable membrane to stretch. Thevolumetric flow rate at which the inflation fluid escapes from theinterior volume of the downstream balloon 107 into the intravascularenvironment may increase as the balloon 107 expands. In someembodiments, the pores 126 may allow for a constant or substantiallyconstant volumetric flow rate of fluid across the pores 126 over a rangeof pressures of the interior volume. The volumetric flow rate out of thedownstream balloon 107 may be maximized at a certain levels ofpressurization or volumetric flow rates of inflation fluid into thedownstream balloon 107. The inflation fluid may be introduced into theinterior volume of the downstream balloon 107 at a volumetric flow ratethat is greater than the volumetric flow rate at which the inflationfluid flows through the pores 126, such that the downstream balloon 107may be inflated even while fluid escapes or leaks through the pores 126.In some implementations, the downstream balloon 107 may be inflatedusing an inflation fluid (for example, saline) that does not comprisethe therapeutic agent. The inflation fluid may be switched over to thetherapeutic solution or the therapeutic agent may be added to theinflation fluid after the downstream balloon has been inflated and/orthe blood vessel has been sealed from retrograde blood flow. Staggeringthe delivery of the therapeutic agent may conserve the therapeutic agentand/or may prevent, reduce, or minimize the amount of therapeutic agentthat is released into the blood stream before the downstream fluid sealis fully formed with the blood vessel.

The pores 126 of the downstream balloon 107 may be disposed uniformlyacross the surface or a portion of the surface of the downstream balloon107. In some embodiments, the pores 126 may be disposed in a centralportion of the downstream balloon 107 relative to the longitudinal axis.For example, in some embodiments, the length of the downstream balloon107 may be configured such that the downstream balloon 107 spans theentire length of an aneurysm 202 or target section of a blood vessel 200and may create a sealed spaced 140 within the aneurysm or section ofblood vessel 200 when the downstream balloon 107 is expanded to aminimal diameter, as illustrated in FIG. 3A. The downstream balloon 107may form a fluid seal with the inner diameter of the blood vessel atpoints proximal to and/or distal to the aneurysm. The expandablemembrane of the downstream balloon 107 may be configured not to expandradially outward into the sealed space 140 between proximal and distalsealing points, to expand partially into the sealed space 140, or toexpand entirely into the sealed space 140 such that the outer surface ofthe downstream balloon 107 conforms to the shape of the aneurysm 202,depending on the properties (for example, elasticity) of the expandablemembrane of the downstream balloon 107. In some embodiments, thedownstream balloon 107 may be compliant enough to conform to the shapeof the aneurysm 202 and blood vessel wall 200, as depicted in FIG. 3A.In some embodiments, the expanded downstream balloon 107 may somewhatexpand the diameter of the blood vessel wall proximate to where thedownstream balloon 107 forms fluid seals with the aneurysm 202. Thepores 126 may be disposed along a central portion configured to bepositioned between a proximal fluid seal and a distal fluid seal suchthat at least a portion of the pores 126 are in fluid communication withthe sealed space 140 and allow delivery of the therapeutic inflationfluid into the sealed space 140 or to a tissue within the sealed space.In some embodiments, any remaining pores 126 of the downstream balloon107 which are not in fluid communication with the sealed space 140 maybe disposed in a configuration on the downstream balloon 107 such thatthe pores 126 are configured to be pressed against the blood vessel 200wall in an expanded configuration. When the downstream balloon 107 isexpanded, the counter pressure of the blood vessel wall against theouter diameter of the downstream balloon 107 may effectively seal thepores 126 in contact with the blood vessel wall from the intravascularenvironment such that fluid may not flow at any substantial flow ratethrough those pores 126. This configuration may prevent or minimizedelivery of therapeutic agent into non-targeted volumes of the bloodvessel and/or into downstream portions of the blood vessel in which thetherapeutic agent may be diffused into the bloodstream within thedownstream vasculature. In some embodiments, contact between thetherapeutic agent within the inflation fluid with the tissue sealedagainst the pores 126 may be used to treat the blood vessel wall. Insome embodiments a plurality of the pores 126 may be spaced at a highdensity over an area configured to be pressed into contact with theblood vessel wall, such as a portion of the aneurysm. In someembodiments, the pores 126 may be brought into close proximity (forexample, no more than 0.3 mm, 0.2 mm, 0.1 mm, 0.075 mm 0.05 mm, 0.025mm, 0.001 mm, etc.) to the target blood vessel tissue but not intosubstantial contact, reducing the volume of the sealed space 140 betweenthe expandable membrane of the downstream balloon 107 and the bloodvessel wall.

In some embodiments, the pores 126 may be disposed on the downstreamballoon 107 along a distal portion of the downstream balloon 107, asillustrated in FIG. 3B. The downstream balloon 107 may be positioned andexpanded near a proximal edge of an aneurysm or target section of ablood vessel, causing the balloon to form a fluid seal at a proximaledge of the aneurysm or target section or proximal thereto. The distalportion of the downstream balloon 107 on which the pores 126 aredisposed may be positioned distally to the proximal fluid seal formed bythe downstream balloon 107, such that at least a portion of the pores126 are in fluid communication with a sealed volume 142 between theproximal seal formed by the downstream balloon 107 and a distal sealformed by the upstream balloon 105. The portion of the downstreamballoon 107 proximal to the distal portion may comprise no pores 126 ormay comprise less pores 126 than the distal portion. In someembodiments, distal portion may be defined as a portion of the balloongenerally distal to a maximum expanded diameter of the downstreamballoon 107. Some of the pores 126 may be configured to be pressedagainst the blood vessel wall where the proximal fluid seal is formedsuch that the counter pressure of the blood vessel wall effectivelyseals those pores 126 from the intravascular environment, as describedelsewhere herein. This configuration may prevent or minimize delivery oftherapeutic agent into downstream portions of the blood vessel in whichthe therapeutic agent may be diffused into the bloodstream within thedownstream vasculature. In some embodiments, the downstream balloon 107may be configured to be positioned entirely downstream of the aneurysmcreating a sealed volume 142 between the upstream balloon 105 and thedownstream balloon 107 which confines the aneurysm.

In some embodiments, as schematically illustrated in FIG. 3C, thedownstream balloon 107 may comprise a length less than a length of theaneurysm and may be positioned entirely within the aneurysm. Theexpanded configuration of the downstream balloon 107 may place theexpandable membrane of the downstream balloon in contact with or inclose proximity to the blood vessel wall of the aneurysm. The deliverycatheter 100 may be configured to position the downstream balloon 107within the aneurysm, such that a midpoint along the length of theballoon 107 is longitudinally aligned substantially with a midpoint ofthe aneurysm or the midpoint of the balloon 107 may be positioned withina proximal or distal portion of the aneurysm. The downstream balloon 107may be positioned entirely within the length of the aneurysm or theballoon 107 may be positioned partially within the aneurysm andpartially outside the aneurysm. In other embodiments, the upstreamballoon 105 may be a weeping balloon in addition to or alternatively tothe downstream balloon 107 and comprise some or all of the same orsimilar features as described with respect to the downstream balloon107.

In some embodiments, including that shown in FIG. 2A and optionallythose shown in FIGS. 2B and 2C, the upstream balloon 105 is connected tothe downstream balloon 107 in a fixed spatial relationship, separated bythe intermediate shaft segment 120. The length of the intermediate shaftsegment 120 may be configured to position the downstream balloon 107 aparticular distance downstream from the upstream balloon 105. Forexample, the upstream balloon 105 may be anchored within the abdominalaorta between the renal arteries. The upstream balloon 105 may occludeantegrade blood flow from the descending aorta and retrograde blood flowfrom the renal arteries from flowing toward the downstream balloon 107.The length of the intermediate shaft segment 120 may be configured toposition the downstream balloon 107 near or adjacent to a typicallocation of an abdominal aortic aneurysm, as in one of theconfigurations described with respect to FIGS. 3A-3C. As describedelsewhere herein, the delivery catheter 100 may be configured toposition the downstream balloon 107 across an aneurysm, if the length ofthe balloon 107 is substantially the same as or greater than the lengthof the aneurysm, or near a downstream edge of the aneurysm. In someimplementations, the length of the downstream balloon 107 may be lessthan the length of the aneurysm. In some implementations, the size (forexample, length) and/or positioning of the downstream balloon 107 (forexample, the length of the intermediate shaft segment 120) may depend onthe size of the aneurysm and/or the stage of the aneurysm progression.The abdominal aortic aneurysm may increase in size (and correspondinglength of the blood vessel) over time. A user may select from variousconfigurations of delivery catheters 100 which are configured foraneurysms of different sizes, positions, and/or stages of progression.

In some embodiments, the separation distance of the upstream balloon 105and the downstream balloon 107 may be adjustable. For example, in theembodiments illustrated in FIGS. 2B and 2C, the secondary shaft 114 mayoptionally be freely translatable within the main shaft 110 along thelongitudinal axis of the delivery catheter 100 such that the distancebetween the upstream balloon 105 and the downstream balloon 107 isvariable and adjustable (for example, continuously or incrementally).The distal end of the main shaft 110 may comprise a sealing featurepositioned between an internal diameter of the main shaft 110 and anouter diameter of the secondary shaft 114, which allows the secondaryshaft 114 to axially translate (for example, slide) relative to the mainshaft 110 while preventing or mitigating fluid flow from theintravascular environment into the first inflation lumen 112. Therelative positioning of the main shaft 110 and the secondary shaft 114may be transiently locked in place by a locking mechanism disposed atthe proximal end of the delivery catheter 100. In some embodiments, thesecondary shaft 114 may be prevented from advancing distally beyond adistal threshold relative to the main shaft 110 and/or from beingretracted proximally beyond a proximal threshold relative to the mainshaft 110. For instance, in some embodiments, the upstream balloon 105may not be configured to be proximally withdrawn past the distal end ofthe main shaft 110. The upstream balloon 105 may not be configured (forexample, dimensioned) to be received within the first central lumen 112.In some embodiments, features at the proximal end of the deliverycatheter 100 and/or within the first central lumen 112 between the innerdiameter of the main shaft 110 and the outer diameter of the secondaryshaft 114 (for example, mechanical catches or latches) may prevent axialtranslation in the proximal and/or distal direction beyond a certainpoint.

In some embodiments, the secondary shaft 114 may be removable from thefirst central lumen 112 of the main shaft 110. The secondary shaft 114may be reversibly insertable into and removable from the main shaft 110.The secondary shaft 114 may be configured to be removed only when theupstream balloon 105 is in an unexpanded or compressed configuration. Insome implementations, the secondary shaft 114 may be inserted into themain shaft 110 and advanced distally beyond the distal end of the mainshaft 110 after the main shaft 110 has been navigated to the target siteor general target area of the vasculature. In some implementations, themain shaft 110 may be advanced over the secondary shaft 114 after thesecondary shaft 114 has been navigated to the target site or generaltarget area of the vasculature. The delivery catheter 100 may be removedfrom the vasculature after the therapeutic procedure as a single unit orthe main shaft 110 or secondary shaft may be removed sequentially in anyorder. The expandable members 104, 106 may be compressed or unexpanded(for example, the balloons 105, 107 may be deflated) prior to removal ofthe delivery device 100 or its constituent components from thevasculature.

In some embodiments, one or more of the components of the deliverycatheter 100 may comprise radiopaque materials or radiopaque elements(for example, radiopaque rings) may be added to the delivery catheter100. For example, radiopaque rings may be added to one or more of thedistal end of the main shaft 110, the distal end of the secondary shaft114, the distal and/or proximal ends of the intermediate shaft segment120, and the upstream or downstream balloons 105, 107 (for example, atproximal and distal ends of the balloons). Use of radiopaque elements orother detectable elements may allow for visual tracking of the deliverycatheter within the vasculature, such as through radioscopy or othersuitable imaging means, and/or may allow for evaluation of thepositioning of the upstream balloon 105 and/or the downstream balloon107 within the vasculature. In some implementations, the inflation fluidof one or both of the upstream balloon 105 and downstream balloon 107may include a contrast agent. Use of the contrast agent may allow theuser to evaluate the state or amount of inflation of the balloon, mayallow the user to determine if the balloon has occluded the bloodvessel, and/or, in the case of the downstream balloon 107, may allow theuser to monitor the delivery of the therapeutic agent into the bloodvessel and/or aneurysm.

In some embodiments, the delivery catheter 100 may be useable with oneor more guidewires for facilitating the introduction and/or navigationof the device into and within the vasculature. In some embodiments, aguidewire may be received within the first central lumen 112, such aswhen the secondary shaft 114 is removable from the first central lumen112, and/or a guidewire may be received within the secondary centrallumen 116. In some embodiments, the lumen, such as the secondary centrallumen 116, may be configured to prevent a guidewire from extendingdistally beyond a certain point along the length of the lumen. Forexample, the secondary lumen may be dimensioned with a catch or atapered or step-down in diameter that prevents the guidewire fromextending distally any further. The secondary central lumen 116 may beopen or closed at a distal end of the secondary shaft 114. The guidewiremay be configured to extend distally beyond the distal end of thesecondary shaft 114 in embodiments where the central lumen is opendistally to the intravascular environment. In some implementations, thedelivery catheter 100 may be introduced over the guidewire after theguidewire has been navigated to or near the target site. In someimplementations, the delivery catheter 100 may be capable of beingnavigated to the target site without use of a guidewire. For example,for applications within the abdominal aorta, the delivery catheter 100may be readily pushed into position via access through the femoralartery without the need for steerability. In some embodiments, thedelivery catheter 100 may comprise steerable components, such as themain shaft 110, which may be configured to bend near a distal end 102 ofthe device. The delivery catheter 100 may comprise one or more pullwires which extend from or from near a distal end 102 of the device to aproximal end of the device. Operation of a control on the proximal endof the delivery catheter 100 may be configured to bend a distal portionof the delivery catheter 100 in one or more directions. Steerability ofthe delivery catheter 100 may facilitate the introduction and/ornavigation of the delivery catheter 100.

In some embodiments, such as that depicted in FIG. 2C, the distal end ofthe secondary central lumen 116 may be open to the intravascularenvironment. In some embodiments, the distal end of the main internallumen 112 may be open, at least partially, to the intravascularenvironment. In these embodiments, some blood may flow proximallythrough these lumens across the delivery catheter device. The deliverycatheter 100 may be configured such that blood flow through these lumensdoes not enter the sealed volume 142 between the expanded upstreamballoon 105 and expanded downstream balloon 107, as described elsewhereherein. In some embodiments, the blood flow through the internal lumensof the delivery catheter 100 may be in fluid communication with aproximal end of the delivery catheter 100. In some embodiments, thedelivery catheter 100 may comprise one or more ports (not shown) influid communication with the intravascular environment, positionedproximally to the downstream balloon 107, such that the blood flow, orat least a portion thereof, may be returned to blood vessel downstreamof the sealed volume 142. The first central lumen 112 and/or thesecondary central lumen 116 may be sealed at a proximal end during useto promote blood flow into the downstream intravascular space ratherthan through the proximal end of the delivery catheter 100. In someimplementations, blood flow through these lumens may be negligible. Forinstance, the diameter of the lumens may be small enough such thatsignificant volumes of blood are not driven through the lumens duringuse of the delivery catheter 100. In some implementations, blood flowthrough these lumens may be non-negligible. In some embodiments, thelumens may be used to maintain blood flow through the aorta during theprocedure and may facilitate prolonging the duration of blood occlusionand the therapeutic treatment.

In some embodiments, the lumens described elsewhere herein may not beformed from the concentric positioning of two or more shafts, but rathermay be configured as internal lumens formed as channels within thebodies of one or more unitary shafts. For example, the main shaft 110may extend from a proximal end of the device, through a center of thedownstream balloon 107, to the upstream balloon 105. The main shaft 110may comprise a plurality of internal lumens (for example, non-concentriclumens) formed within the body material of the main shaft 110. Theinternal lumens may run substantially parallel to one another. Theinternal lumens may extend to different lengths along the longitudinalaxis of the delivery catheter 100. The internal lumens may be in fluidcommunication with different components of the delivery catheter 100.For example, one internal lumen may be in fluid communication with theupstream balloon 105 and another internal lumen may be in fluidcommunication with the downstream balloon 107. The main shaft 110 orother shaft components may comprise additional lumens beyond what isdescribed elsewhere herein. For example, the delivery catheter 100 mayhave lumens configured for receiving guidewires and/or lumens configuredfor providing aspiration.

For instance, in some embodiments, the delivery catheter 100 maycomprise an aspiration lumen in fluid communication with an aspirationport positioned along the intermediate shaft segment 120. FIG. 2Bschematically depicts a supplemental internal lumen 138 in fluidcommunication with a supplemental fluid port 139 disposed on theintermediate shaft segment 120. The supplemental internal lumen 138 maybe used as an aspiration lumen or as a drug delivery lumen, as describedelsewhere herein. In some implementations, the aspiration lumen may beused to aspirate the intravascular environment within a sealed volumebetween the upstream balloon 105 and the downstream balloon 107.Aspiration of fluid (for example, blood) from the sealed volume beforeand/or during delivery of the therapeutic agent may increase the volumeand/or concentration of therapeutic agent that may be delivered to thesealed volume using the delivery device 100. In some implementations,the sealed volume 142 may be aspirated after treatment using thetherapeutic agent and before the upstream balloon 105 and/or thedownstream balloon 107 is deflated. Removal of the therapeutic agentfrom the intravascular environment prior to restoring blood flow mayeliminate, reduce, or mitigate any downstream and/or non-localizedeffects of releasing the therapeutic agent into the blood stream. Insome embodiments, the supplemental internal lumen 138 in fluidcommunication with the sealed volume 142 may be used to deliver thetherapeutic agent into the sealed volume 142 in addition to oralternatively to a weeping balloon.

FIGS. 4A-4C schematically illustrates examples of a delivery catheter100 comprising a third expandable member 108. The third expandablemember 108 may be an inner balloon 109 as shown in FIG. 4A. FIGS. 4A and4B may comprise features that are the same or relatively similar tothose described with respect to FIG. 2A, and FIG. 4B may comprisefeatures that are the same or relatively similar to those described withrespect to FIG. 2C, except for the inclusion of the inner balloon 109.The inner balloon 109 may be positioned entirely within the interior ofthe downstream balloon 105 as shown in FIGS. 4A-4C. The inner balloon109 may be in fluid communication with a tertiary inflation lumen 134.As shown in FIG. 4A, the tertiary inflation lumen 134 may be formedwithin the main shaft 110. In some embodiments, the tertiary inflationlumen 134 may be formed radially inside the first inflation lumen 113.The tertiary inflation lumen 134, may be formed by the first centrallumen 112, as shown in FIG. 4A. In some embodiments, the tertiaryinflation lumen 134 may be formed from a separate tubular component thatis carried within the first central lumen 112 of the main shaft 110.

The inner balloon 109 may comprise an expandable membrane. Theexpandable membrane of the inner balloon 109 may comprise the sameand/or different material(s) as the expandable membrane of thedownstream balloon 107 and/or the upstream balloon 105. In someembodiments, such as that shown in FIG. 4A, the expandable membrane iscoupled to (for example, at or near) the secondary shaft 114 forming afluid tight seal with the secondary shaft 114 such that an interiorvolume of the inner balloon 109 may be pressurized. Introduction ofinflation fluid into the upstream balloon 105 may cause the innerballoon 109 to expand radially outward between the tertiary inflationlumen 134 and the distal fluid tight seal. The distal end of theexpandable membrane of the inner balloon 109 may be substantiallylongitudinally aligned with the distal end of the expandable membrane ofthe downstream balloon 107 or may be coupled to the secondary shaft 114at a point proximal to that where the expandable membrane of thedownstream balloon 107 is coupled to the secondary shaft 114.

In some embodiments, as shown in FIG. 4B, proximal and distal ends ofthe expandable membrane of the inner balloon 109 may be coupled to thesecondary shaft 114 to form fluid-tight seals around the outer diameterof the secondary shaft 114. The distal end of the expandable membrane ofthe inner balloon 109 may be substantially longitudinally aligned withthe distal end of the expandable membrane of the downstream balloon 107or may be coupled to the secondary shaft 114 at a point proximal to thatwhere the expandable membrane of the downstream balloon 107 is coupledto the secondary shaft 114. The proximal end of the expandable membraneof the inner balloon 109 may be substantially longitudinally alignedwith the proximal end of the expandable membrane of the downstreamballoon 107 or may be coupled to the secondary shaft 114 at a pointdistal to the proximal end of the downstream balloon 109. Inflationfluid may be introduced to pressurize the interior volume of the innerballoon 109 allowing the expandable membrane to expand radially outwardbetween the proximal and distal ends of the expandable membrane of theinner balloon 109 upon the introduction of the inflation fluid.Inflation fluid may be introduced into the interior of the inner balloon109 through one or more tertiary inflation ports 136 formed in thesidewall of the secondary shaft 114. The tertiary inflation lumen 134may be disposed within the secondary shaft 114 rather than the mainshaft 110. The tertiary inflation ports 136 may pass through a sidewallof the secondary shaft 114. In some embodiments, a plurality of tertiaryinflation ports 136 may be spaced longitudinally along the secondaryshaft 114 between the proximal and distal ends of the expandablemembrane of the inner balloon 109. In some embodiments, a plurality oftertiary inflation ports 136 may be spaced radially around the outerdiameter of the secondary shaft 114.

In some embodiments, as shown in FIG. 4C, the tertiary inflation ports136 are formed in a sidewall of the main shaft 110 and the inner balloon109 may be coupled at proximal and distal sealing points to an outerdiameter of the main shaft 110. In some embodiments, the inner balloon109 may be a generally toroidal balloon, as described elsewhere hereinwith respect to downstream balloon 107. The toroidal inner balloon 109may be disposed within the interior volume of the downstream balloon107. In some embodiments, the inner surface of the expandable membraneof the toroidal inner balloon 109 may be coupled at a proximal end,distal end, or along a length or portions of the length of the innersurface to the main shaft 110 or secondary shaft 114, depending on theconfiguration of the delivery catheter 100. In some embodiments, theinner toroidal balloon 109 may be coupled to the expandable membrane ofthe downstream balloon 107. In some embodiments, the inner toroidalballoon 109 may be coupled to a shaft and the expandable membrane of thedownstream balloon 107. In some embodiments, the toroidal inner balloon109 may be free-floating within the interior volume of the downstreamballoon 107. In some embodiments, the downstream balloon 107 may be agenerally toroidal balloon as described elsewhere herein and the innerballoon 109 may be disposed within the annular interior volume of thedownstream balloon 107. The generally toroidal inner balloon 109 may becoupled to an inner surface and/or an outer surface of the expandablemembrane of the generally toroidal downstream balloon 107 or the innerballoon 109 may be free-floating within the annular interior volume ofthe downstream balloon 107.

The inner balloon 109 may facilitate the expansion of the downstreamballoon 107 and/or the expulsion of inflation fluid (includingtherapeutic agent) from the downstream balloon 107. The inclusion andinflation of an inner balloon 109 may advantageously reduce the volumeof inflation fluid within the downstream balloon 107 necessary to expandthe downstream balloon and/or expel inflation fluid through the pores126 of the downstream balloon 107. The reduction of inflation fluid usedwithin the downstream balloon 109 may conserve the therapeutic agent.The use of the inner balloon 109 may reduce the pressure within theinterior of the downstream balloon 107 at which inflation fluid isexpelled through the pores 126. In some implementations, a volume ofinflation fluid may be introduced into the interior volume of thedownstream balloon 107 which is insufficient to fully expand thedownstream balloon 107 or to expand the downstream balloon 107 to theinner diameter of the target blood vessel. The inner balloon 109 may beinflated, pressing the volume of inflation fluid within the interior ofthe downstream balloon 107 against the expandable membrane of thedownstream balloon 107 and causing the downstream balloon 107 to expand.In some embodiments, the volume of inflation fluid may be deliveredthrough the pores 126 at a substantial (for example, non-negligible)rate as soon as the combined volume of the inner balloon 109 and thevolume of inflation fluid within the downstream balloon 107 issubstantially equal to the interior volume of the downstream balloon 107or as soon as the reduction of volume available for the volume ofinflation fluid is small enough that it causes the internal pressurewithin the downstream balloon 107 to surpass a minimum threshold.

Any or all of the balloons described herein may comprise various shapes.The shapes of the device balloons may be the same or different. Invarious embodiments, the shape of the balloon may be defined by asurface of revolution. In some embodiments, the balloons may comprise asubstantially spherical shape. In some embodiments, the balloons maycomprise a spheroid shape, such as a prolate spheroid shape or an oblatespheroid shape. The longitudinal axis of the spheroid may be alignedwith the longitudinal axis of the delivery catheter 100. In variousembodiments, the length of the balloon may be larger than a diameter ofthe balloon in its expanded configuration (for example, a prolatespheroid). In some embodiments, the balloons may comprise a pointedfootball shape. In some embodiments, the balloons may comprise acylindrical shape. The balloons may comprise distinct proximal anddistal surfaces extending from the longitudinal axis of the deliverydevice 100 to form an edge with an outer surface of the balloon. Theproximal and/or distal surfaces may be substantially flat, generallyconcave, and/or generally convex. The outer surface of the balloons mayextend to a diameter greater than, substantially equal to, or less thana diameter of the proximal surface and/or the distal surface. The outersurface may be generally flat, concave, or convex. In some embodimentsthe pores 126 of the weeping balloon may be only disposed on the outersurface of the balloon or on an outer surface and only one of theproximal and distal surfaces (for example, the distal surface of thedownstream balloon 107). In some embodiments, the downstream balloon 107may comprise one or more inner layers including inner pores. In someembodiments, the inner pores may generally comprise diameters greaterthan or equal to the diameter of the pores 126. The inner pores mayserve as baffles which may help facilitate uniform distribution of theinflation fluid (and therapeutic agent) within the interior of thedownstream balloon 107.

The outer diameter of the upstream balloon 105 in an expandedconfiguration (for example, at its widest point) may be at leastapproximately 1.5 cm, 1.75 cm, 2.0 cm, 2.25 cm, 2.5 cm, 3.0 cm, or 3.5cm. The outer diameter of the upstream balloon 105 in an expandedconfiguration may be configured to match or slightly exceed the diameterof a healthy abdominal aorta (for example, near the renal arteries). Insome embodiments, the downstream balloon 107 may be configured to expandto the diameter of a health aorta or slightly exceed the diameter of ahealthy aorta such that it may form a fluid seal with the aortadownstream of and optionally upstream of an abdominal aortic aneurysm orwith a relatively non-enlarged portion or portions of the aneurysm (forexample, near the proximal and/or distal edges of the aneurysm). In suchembodiments, the outer diameter of the downstream balloon 107 in anexpanded configuration may be substantially equal to the outer diameterof the upstream balloon 105 or slightly larger than the outer diameterof the upstream balloon 105 in an expanded configuration. The outerdiameter of the downstream balloon 107 in an expanded configuration maybe at least approximately 1.5 cm, 1.75 cm, 2.0 cm, 2.25 cm, 2.5 cm, 3.0cm, 3.5 cm, or 4.0 cm. In embodiments, where the downstream balloon 107is configured to be expanded well into the sac of the abdominal aorticaneurysm, the downstream balloon 107 may have an outer diameter in theexpanded configuration substantially larger than that of the upstreamballoon 105. The outer diameter of the downstream balloon 107 in anexpanded configuration may be at least approximately 1.5 cm, 1.75 cm,2.0 cm, 2.25 cm, 2.5 cm, 3.0 cm, 3.5 cm, or 4.0 cm, 4.5 cm, 5.0 cm, 5.5cm, 6.0 cm, 6.5 cm, 7.0 cm, 7.5 cm, or 8.0 cm. In some embodiments, theexpanded diameter of the downstream balloon 107 may be at least about100%, 125%, 150%, 175%, 200%, 300%, 400%, or 500% the expanded diameterof the upstream balloon 105. In some embodiments, the total volume ofthe downstream balloon 107 (for example, in an expanded configuration)or of the holding capacity of deliverable fluid of the delivery catheter100 (for example, the interior volume of the downstream balloon 107 andthe first inflation lumen 113) may be at least about 1 mL, 2 mL, 3 mL, 5mL, 10 mL, 20 mL, 30 mL, 40 mL, 50 mL, 60 mL, 70 mL, 80 mL, 90 mL, 100mL, 125 mL, 150 mL, 175 mL, or 200 mL.

Delivery catheters 100 in which the downstream balloon 107 expands intoor is pressed into contact with the abdominal aortic aneurysm may beparticularly suited for aneurysms that are less prone to rupture. Insome instances, the risk of rupture may be characterized by the size(for example, maximal diameter) of the aneurysm. Smaller aneurysms (forexample, no greater than about 6 cm, 5 cm, 4 cm, or 3 cm) may be lessprone to rupture. Abdominal aortic aneurysms may tend to grow in sizeover time and become more prone to rupture. The blood vessel wall of theaneurysm may weaken as the aneurysm grows. In some implementations, thedelivery catheters 100 described herein, may be particularly useful forearly interventional treatment of diagnosed abdominal aortic aneurysms.

The length of the downstream balloon 107 may be at least about 0.5 cm, 1cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, or 10 cm. In someembodiments, the length of the downstream balloon 107 may be configuredto span the length of the abdominal aortic aneurysm, as describedelsewhere herein. In some embodiments, the abdominal aortic aneurysm maybe relatively small or in an early-stage of development. In someembodiments, the length of the upstream balloon 105 may be the same asthe length of the downstream balloon 107 or it may be shorter than thelength of the downstream balloon 107. In some embodiments, the length ofthe upstream balloon 105 may be at least about 0.5 cm, 1 cm, 1.5 cm, 2cm, 2.5 cm, or 3 cm. In some embodiments, the upstream balloon 105 maycomprise a generally spherical shape and the downstream balloon 107 maycomprise a generally prolate spheroid shape.

In embodiments comprising an inner balloon 109, the inner balloon 109may be the same or a different shape as the downstream balloon 107. Theinner balloon 109 may comprise an expanded diameter the same as or lessthan that of the downstream balloon 107. The inner balloon 109 maycomprise a length the same as or less than that of the downstreamballoon 105. The inner balloon 109 may comprise a maximum interiorvolume the same as or less than that of the downstream balloon 105. Insome embodiments, the volume, length, and/or expanded diameter of theinner balloon 109 may be no less than approximately 100%, 95%, 90%, 85%,80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of the downstream balloon107. In embodiments, in which the length of the inner balloon 109 isless than the length of the downstream balloon 107, the inner balloon109 may be positioned, with respect to the longitudinal axis, centrallywithin the downstream balloon, or toward the proximal or distal end ofthe downstream balloon 107. The proximal end of the inner balloon 109may or may not be aligned with the proximal end of the downstreamballoon 107. The distal end of the inner balloon 109 may or may not bealigned with the distal end of the downstream balloon 107.

In some embodiments, the unexpanded diameters of the upstream balloon105, downstream balloon 107, and/or the inner balloon 109 of thedelivery catheter 100 may be no greater than about 0.5 mm, 1 mm, 2 mm, 3mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, or 10 mm. The unexpandeddiameter of one or more of the balloons may be configured to be receivedwithin the lumen of a concentrically surrounding shaft or access sheath.

In some embodiments the weeping balloon (for example, downstream balloon107) may comprise at least 5, 10, 20, 30, 40, 50, 100, 200, 300, 500, or1000 pores 126. The diameter (or longest dimension) of the individualpores 126 may be the same or may be different. The diameter of the pores126 (for example, in an expanded configuration) may be no greater thanapproximately 0.01 mm, 0.02 mm, 0.03 mm, 0.05 mm, 0.04 mm, 0.05 mm, 0.06mm, 0.07 mm, 0.08 mm, 0.09 mm, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm,0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, or 1 mm. In some embodiments, thediameter of the pores 126 in the expanded configuration may be at leastabout 1×, 1.25×, 1.5×, 1.75×, 2×, 3×, 4×, 5×, or 10×, the diameter ofthe pores 126 in the unexpanded configuration. The pores 126 may be thesame size regardless the state of expansion in some embodiments,particularly if downstream balloon 107 comprises a non-compliantexpandable membrane. In some embodiments, the pores 126 may be disposedover an entire length of the downstream balloon 107. In someembodiments, the pores 126 may be disposed over only about the middle20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% of the length of thedownstream balloon 107 (for example, in an expanded configuration). Insome embodiments, the pores 126 may be disposed only over a distalportion of the length of the downstream balloon 107, the distal portioncomprising no more than about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or95% of the length of the downstream balloon 107 (for example, in anexpanded configuration).

In some embodiments, the outer diameter of the main shaft 110 may be nogreater than about 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm,or 10 mm. In some embodiments, the outer diameter of the main shaft 110may be approximately 9 Fr, 10 Fr, 11 Fr, 12 Fr, 13 Fr, 14 Fr, 15 Fr, 16Fr 17 Fr, or 18 Fr. The main shaft 110 may have a sidewall thickness ofno greater than approximately 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm,0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm, 1.25 mm, 1.5 mm, 1.75 mm, or 2.0mm. The secondary shaft 114 may comprise an outer diameter substantiallyequal to or slightly less than the inner diameter of the main shaft 110.In some embodiments, the length of the delivery catheter 100 from itsproximal end to its distal end 102 may be at least about 20 cm, 25 cm,30 cm, 35 cm, 40 cm, 45 cm, or 50 cm.

The various components of the delivery catheter 100 may be fabricatedfrom one or more materials known in the art of catheter design. Thematerials, particularly those configured to be placed in contact withthe intravascular environment, may be fabricated from biocompatiblematerials. In some embodiments, one or more components of the deliverycatheter, such as the main shaft 110 and/or secondary shaft 114, maycomprise polyurethane (PU), polyethylene (PE), polyvinylchloride (PVC),polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), otherfluoropolymers, polyether block amide (for example, PEBAX® orVestamid®), nylon, etc. In various embodiments, the shafts and/orballoons may be chemically and/or mechanically treated/processed (forexample, plasma etched) or coated to provide biocompatibility ormechanical properties (for example, lubricious and/or hydrophilicsurface properties). For example, one or more components of the deliverycatheter 100 may be coated with a formulation comprising polyethyleneglycol (PEG).

In some embodiments, the delivery catheter 100 may comprise a handle atits proximal end. The main shaft 110 of the delivery catheter 100 mayextend from a distal end of the handle. The main shaft 110 may continuethrough the handle and/or be in fluid communication with a channelformed within the handle. The handle may comprise a grip portion for theoperator to grasp. The handle may be used to distally advance and/orproximally retract the delivery catheter 100. In embodiments where thedelivery catheter 100 is steerable, the handle may comprise one or morecontrols for steering (for example, bending a distal portion of) thedelivery catheter 100, such as by controlling the extension andretraction of one or more pull wires. In some embodiments, the handlemay comprise one or more fluid ports in fluid communication with one ormore of the internal lumens, such as the first inflation lumen 113 andthe secondary inflation lumen 117. The fluid ports may compriseluer-type connectors for connecting to fluid lines, such as forsupplying inflation fluid to the delivery catheter 100. In someembodiments, the fluid ports may comprise stopcocks or other valves forregulating fluid flow from a fluid supply source into the handle. Thefluid lines may extend to sources of pressurized fluid (for example,inflation fluid) such as a syringe or pump and/or a vacuum source forproviding aspiration. In some embodiments, one more fluid ports may beconfigured to receive a component of the delivery catheter 100. Forexample, in embodiments, in which the secondary shaft 114 is removablefrom the main shaft 110, the secondary shaft 114 may be insertable intoa proximal end of the handle through the fluid port to be received inthe main shaft 110. The secondary shaft 114 may be advanced through thefluid port until it extends distally beyond the main shaft 110. Thehandle may comprise a means for temporarily fixing the relativepositioning of the shafts 110, 114, as described elsewhere herein.Similarly, in some embodiments, a guidewire may be insertable into aproximal end of the handle through one or more fluid ports to bereceived in the first central lumen 112 or the secondary central lumen116. In some embodiments, in which inflation fluid is supplied by a pumpor mechanized syringe, and/or in which aspiration is provided, there maybe a controller for controlling flow rate through the internal lumens.The controller may be remote to the handle or coupled to or integralwith the handle. The handle may comprise one or more controls formodulating (for example, increasing, decreasing, stopping, and/orstarting) the flow rate of the inflation fluid and/or the vacuumpressure supplied to one or more of the internal lumens. In someembodiments, the controls may be remote from the handle (for example,part of a remote controller).

Delivery Methods

In some implementations, the delivery catheter 100, described elsewhereherein, or a device having similar features to the delivery catheter 100may be used to therapeutically treat an aneurysm or a target side of ablood vessel by delivering a therapeutic agent to the aneurysm or targetsite. Described herein is an example of treating an abdominal aorticaneurysm using the delivery catheter 100 to deliver a therapeuticsolution comprising PGG. Variations of the procedure described hereinmay be encompassed. In some implementations, a device different from thedelivery catheter 100 may be used. In some implementations, atherapeutic other than or in addition to PGG may be delivered. In someimplementations, the therapeutic agent may be delivered to another bloodvessel or body lumen other than the aortic artery. In someimplementations, the treatment may be applied for another type ofaneurysm or for treatment of a blood vessel wall or section of bloodvessel that does not comprise an aneurysm, is healthy, suffers from adifferent diseased condition, and/or the therapeutic agent may beintended to be delivered across the blood vessel wall to target thecellular or extracellular environment adjacent the blood vessel.

A method for treating an abdominal aortic aneurysm is described herein.The method may include or omit any of the steps described elsewhereherein described in relation to the delivery catheter 100. In someembodiments, the delivery catheter 100 is introduced into a femoralartery of the patient. The delivery catheter 100 may be introduced withall expandable members (for example, upstream balloon 105 and downstreamballoon 107) in an unexpanded configuration. The delivery catheter 100may be introduced through an optional access sheath. The distal end 102of the delivery catheter 100 may be navigated into the abdominal aortaand the upstream balloon 105 positioned at a point upstream of thetarget abdominal aneurysm. In some embodiments, a guidewire may benavigated to the target location and the delivery catheter 100 may beintroduced over the guidewire as described elsewhere herein. In someembodiments, the delivery catheter 100 may be received over a guidewireand navigated to the target location contemporaneously with theguidewire, using the guidewire to steer the distal end 102 of thedelivery catheter 100. In some embodiments, the delivery catheter 100may be introduced without the use of a guidewire. The upstream balloon105 may be positioned approximately between the renal arteries. Theexpansion of the upstream balloon 105 partially into the renal arteriesmay help anchor the balloon. The total procedure time may besufficiently low (for example, no more than 2-3 min), as describedelsewhere herein, such that occlusion of blood flow to the renalarteries may safely be maintained during the procedure. In someembodiments, the upstream balloon 107 may be anchored downstream of therenal arteries. Anchoring within a location downstream of the renalarteries may allow longer operation times during which blood flow isoccluded. The upstream balloon 105 may be expanded with the introductionof inflation fluid into the upstream balloon 105. The upstream balloon105 may be expanded until the delivery catheter 100 is securely anchoredin the blood vessel and/or until the blood flow downstream of theupstream balloon 105 has been occluded. In some embodiments, theoperation may be performed under indirect visualization, such asradioscopy. A suitable contrast agent for the method of visualization,(for example, radiocontrast media for radioscopy) may be injected intothe blood stream prior to and/or during the operation to visualize bloodflow. Accordingly, the occlusion of the blood flow may be visuallyassessed by indirect visualization.

The downstream balloon 107 may be positioned within, downstream of, oralong a downstream edge of the abdominal aneurysm. In embodiments inwhich the length of the intermediate shaft segment 120 is adjustable,the delivery catheter 100 may be adjusted to position the downstreamballoon 107 in place after the upstream balloon 105 has been anchored inplace. The downstream balloon 107 may be expanded with the introductionof inflation fluid into the upstream balloon 105. The downstream balloon107 may be expanded until retrograde blood flow from downstream of thedownstream balloon 107 is occluded. Injection of a contrast agent intothe bloodstream may be used to confirm occlusion of blood flow asdescribed elsewhere herein. The inflation of the upstream balloon 105and downstream balloon 107 may create a fluidly sealed volume 142 withina section of the blood vessel between the two balloons 105, 107. In someimplementations, the downstream balloon 107 may be inflated immediatelyafter inflation of the upstream balloon 105 to prevent or minimize theamount of retrograde blood flow into the sealed volume prior to thecomplete inflation of the downstream balloon 107. In some embodiments,the upstream balloon 105 and the downstream balloon 107 may each bepartially inflated, sequentially or simultaneously, and then theupstream balloon 105 may be further expanded to occlude antegrade flowfollowed by further expansion of the downstream balloon 107 to occluderetrograde flow. In some embodiments, the downstream balloon 107 may beinflated simultaneously with or prior to the inflation of the upstreamballoon 105.

In some embodiments, the delivery catheter 100 may comprise an innerballoon 109 positioned within the downstream balloon 107, as describedelsewhere herein. In some embodiments, the inner balloon 109 may bepartially or fully expanded before inflation fluid is introduced intothe downstream balloon 107. In some embodiments, the downstream balloon107 may be filled with a volume of inflation fluid prior to orsimultaneously with the inflation of the inner balloon 109. The firstinflation lumen 113 may be configured at a proximal end to preventunintended proximal flow of inflation fluid due to expansion of theinner balloon 109. For example, an inflation fluid line may be clampedor a pressure may be maintained on a syringe to prevent fluid flow ofinflation fluid proximally from the downstream balloon 107 as the innerballoon 109 is expanded. By preventing or inhibiting proximal flow ofinflation fluid, expansion of the inner balloon 109 may better promotethe expulsion of the volume of inflation fluid within the downstreamballoon 107 through the pores 126. In some embodiments, the inflationfluid in communication with the downstream balloon 107 may be switchedover to a solution comprising the therapeutic agent after or duringexpansion of the downstream balloon 107 or the therapeutic agent may beadded into the inflation fluid during or after inflation of thedownstream balloon 107, as described elsewhere herein. In someembodiments, the initial volume of inflation fluid introduced into thedownstream balloon 107 may comprise the therapeutic agent.

Upon inflation of the downstream balloon 107 or the downstream balloon107 and the inner balloon 109, the inflation fluid, or a partial volumethereof, within the downstream balloon 107 may be expelled through thepores 126, or a portion of the pores 126, into the intravascularenvironment. The pores 126 may be positioned on a surface of theexpandable membrane of the downstream balloon 127 so as to deliver atleast some, if not all or a majority of, the delivered inflation fluidinto the sealed volume 142 between the upstream balloon 105 and thedownstream balloon 107 or a sub-volume thereof. The sub-volume may be asealed volume (for example, sealed space 140) formed by the downstreamballoon 107 placed in contact with the blood vessel. In embodimentswithout an inner balloon 109, inflation fluid comprising the therapeuticagent may continue to be supplied to downstream balloon 107 at apressure or volumetric flow rate configured to maintain the downstreamballoon 107 in an expanded configuration after expansion. The deliverydevice 100 may be configured to provide infusion of the therapeuticagent at a constant pressure. The introduction of therapeutic inflationfluid into the downstream balloon 107 may be maintained long enough todeliver the therapeutic inflation fluid through the pores 126 for adesired duration of time and/or to deliver a predetermined volume oftherapeutic inflation fluid through the pores 126. In embodimentscomprising an inner balloon 109, the therapeutic inflation fluid maycontinue to be introduced into the downstream balloon 107 afterinflation of the downstream balloon 107 and the inner balloon 109. Insome embodiments, the volume of inflation fluid within the downstreamballoon 107 may not be replenished as the inner balloon 109 expands toexpel the therapeutic inflation fluid through the pores 126.

In some embodiments, the therapeutic agent may be PGG. The PGG may bedissolved in the therapeutic inflation solution at a final concentrationthat is no less than approximately 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%,0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% (w/v). As described elsewhereherein, higher concentrations of PGG may provide for more effectivetreatment, especially over shorter treatment times. Accordingly, higherconcentrations may allow shorter treatment time. Higher purity PGG maybe less toxic, due to absence of toxic impurities, than lower purityPGG. Accordingly, higher purity PGG may be safer to user at higherconcentrations than lower purity PGG. The PGG may be dissolved in aninflation fluid such as saline (for example, via a hydrolyzer asdescribed elsewhere herein). The volume of delivered therapeuticinflation fluid may be no more than approximately 150 mL, 125 mL, 100mL, 75 mL, 50 mL, 40 mL, 30 mL, 20 mL, 15 mL, 10 mL, 8 mL, 5 mL, 3 mL,or 1 mL. In some embodiments, inflation fluid may be delivered throughthe downstream balloon 107 until a sealed volume, as described elsewhereherein, is filled. In some embodiments, filling of the volume may bedetectable by an increase in resistance (a counter pressure) to thedelivery of inflation fluid. In some embodiments, filling of the volumemay be visually discernable if the inflation fluid comprises adetectable contrast agent. The duration of delivery may be no more thanabout 30 min, 10 min, 5 min, 4 min, 3 min, 2 min, 1 min, 45 seconds, 30seconds, 20 seconds, or 10 seconds. The duration of delivery may beshorter in embodiments in which the renal arteries are occluded by thedelivery catheter 100. In some implementations, procedures involvingaortic occlusions no longer than approximately 10 min may advantageouslybe performed without the need for general anesthesia. The precise volumeof delivered fluid and/or the duration of delivery may depend on thesize of the aneurysm or volume of the targeted section of blood vesselto be treated. In some embodiments, the therapeutic inflation solutionmay be delivered to the downstream balloon 107 at a volumetric flow rateof between approximately 0.05 mL/min and 20 mL/min, 0.1 mL/min and 10mL/min, 0.5 mL/min and 8 mL/min, or 1 mL/min and 5 mL/min, during thedelivery of the therapeutic agent to the blood vessel. In someembodiments, the downstream balloon 107 may be inflated by delivery ofinflation fluid at the same volumetric flow rate at which the inflationfluid is introduced during delivery of the therapeutic agent afterexpansion. In some embodiments, the downstream balloon 107 may beinflated with a volumetric flow rate that is faster than the volumetricflow rate of delivery after expansion. A faster flow rate duringexpansion of the downstream balloon 105 may facilitate expanding theballoon as the inflation fluid leaks through the pores 126.

By expanding the upstream balloon 107 and occluding downstream bloodflow prior to expansion of the downstream balloon 105, the counterpressure needed to cause expansion of the downstream balloon 107 withinthe intravascular environment may advantageously be reduced. After thedownstream blood flow is occluded, the downstream balloon 107 may beexpanded upon exceeding the diastolic blood pressure of the patient (forexample, approximately 60-80 mmHg), whereas if the downstream blood flowis not occluded, the systolic pressure (for example, approximately90-120 mmHg) may need to be exceeded. Thus, occluding the downstreamblood flow prior to expansion (or full expansion) of the downstreamblood flow may facilitate expansion of a weeping balloon, in whichpressure may be continually released, such as downstream balloon 107.

In some embodiments, the blood vessel, or a portion thereof (forexample, the sealed volume 142 between the upstream balloon 105 and thedownstream balloon 107) may be rinsed prior to or after delivery of thetherapeutic agent. A rinsing solution (for example, saline) may beintroduced to the intravascular space through the downstream balloon 107prior to delivery (for example, during expansion as described elsewhereherein) or after delivery of the therapeutic agent. In some embodiments,a rinsing solution may be introduced through a separate internal lumenas described elsewhere herein. For example, a rinsing solution may beintroduced into the sealed volume through a fluid port positioned alongthe intermediate shaft segment 120.

In some embodiments, fluid within the blood vessel, or a portion thereof(for example, the sealed volume 142 between the upstream balloon 105 andthe downstream balloon 107), may be aspirated through the deliverycatheter 100. For example, aspiration may be provided through a separateinternal lumen through an aspiration port positioned along theintermediate shaft segment 120, as described elsewhere herein. In someembodiments, the sealed volume 142 may be aspirated to remove any bloodand/or rinsing solution prior to delivery of the therapeutic agent. Insome embodiments, the sealed volume 142 may be rinsed contemporaneously(for example, continuously or intermittently) with the delivery of thetherapeutic agent, such that fresh volumes of the therapeutic inflationfluid are introduced into the intravascular space. In some embodiments,the sealed volume 142 may be aspirated to remove the therapeutic agentand/or rinsing solution prior to deflating the upstream balloon 105and/or downstream balloon 107. Aspiration may advantageously preventnon-targeted delivery of the therapeutic agent to other parts of theblood vessel or body by releasing the therapeutic agent into the bloodstream upon deflation of the balloons 105, 107.

Upon completion of the therapeutic treatment the expandable members 104,106 may be compressed or de-expanded for removal of the deliverycatheter 100 from the vasculature. The upstream balloon 105 anddownstream balloon 107, and/or the inner balloon 109 may be deflated bywithdrawing the inflation fluid proximally through the first inflationlumen 113 and secondary inflation lumen 117, respectively. In someembodiments, the downstream balloon 107 may be deflated, or at leastpartially deflated, by forcing all or a portion of the inflation fluidthrough the pores 126 of the expandable membrane without replenishingthe inflation fluid within the downstream balloon 107. The upstreamballoon 105 may be deflated prior to, after, or substantiallysimultaneously with the deflation of the downstream balloon 107. Theinner balloon 109, when present, may be deflated prior to orsubstantially simultaneously with the downstream balloon 107. Upondeflation of the balloons, blood flow may be restored to portions of theaorta downstream of each balloon. The total duration of time for whichblood flow is occluded may be no greater than about 30 min, 10 min, 5min, 4 min, 3 min, 2 min, 1 min, 45 seconds, 30 seconds, 20 seconds, or10 seconds.

The delivery catheter 100 may be removed from the body by withdrawingthe delivery catheter 100 proximally through the vascular access point.In some embodiments in which the delivery catheter 100 comprisesmultiple components (for example, main shaft 110 and secondary shaft 114are separable) or is used in conjunction with ancillary components (forexample, an access sheath and/or guidewire), the components may bewithdrawn in a reverse order in which they were introduced, thecomponents may be withdrawn in a different order, and/or the componentsor subgroups thereof may be withdrawn contemporaneously. In someembodiments, one or both of the expandable members 104, 106 may need tobe placed into an unexpanded configuration or at least partiallyde-expanded in order to withdraw the delivery catheter 100.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs. All patents, applications,published applications, and other publications are incorporated byreference in their entirety. In the event that there is a plurality ofdefinitions for a term herein, those in this section prevail unlessstated otherwise.

Where the compounds disclosed herein have at least one chiral center,they may exist as individual enantiomers and diastereomers or asmixtures of such isomers, including racemates. Separation of theindividual isomers or selective synthesis of the individual isomers isaccomplished by application of various methods which are well known topractitioners in the art. Unless otherwise indicated, all such isomersand mixtures thereof are included in the scope of the compoundsdisclosed herein. Furthermore, compounds disclosed herein may exist inone or more crystalline or amorphous forms. Unless otherwise indicated,all such forms are included in the scope of the compounds disclosedherein including any polymorphic forms. In addition, some of thecompounds disclosed herein may form solvates with water (i.e., hydrates)or common organic solvents. Unless otherwise indicated, such solvatesare included in the scope of the compounds disclosed herein.

The skilled artisan will recognize that some structures described hereinmay be resonance forms or tautomers of compounds that may be fairlyrepresented by other chemical structures, even when kinetically; theartisan recognizes that such structures may only represent a very smallportion of a sample of such compound(s). Such compounds are consideredwithin the scope of the structures depicted, though such resonance formsor tautomers are not represented herein.

Isotopes may be present in the compounds described. Each chemicalelement as represented in a compound structure may include any isotopeof said element. For example, in a compound structure a hydrogen atommay be explicitly disclosed or understood to be present in the compound.At any position of the compound that a hydrogen atom may be present, thehydrogen atom can be any isotope of hydrogen, including but not limitedto hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, referenceherein to a compound encompasses all potential isotopic forms unless thecontext clearly dictates otherwise.

The term “Solvate” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitationto the compound formed by the interaction of asolvent and a compound described herein or salt thereof. Suitablesolvates are pharmaceutically acceptable solvates including hydrates.

The term “pharmaceutically acceptable salt” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitationto salts that retainthe biological effectiveness and properties of a compound and, which arenot biologically or otherwise undesirable for use in a pharmaceutical.In many cases, the compounds disclosed herein are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. Pharmaceutically acceptableacid addition salts can be formed with inorganic acids and organicacids. Inorganic acids from which salts can be derived include, forexample, hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, and the like. Organic acids from which salts canbe derived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceuticallyacceptable base addition salts can be formed with inorganic and organicbases. Inorganic bases from which salts can be derived include, forexample, sodium, potassium, lithium, ammonium, calcium, magnesium, iron,zinc, copper, manganese, aluminum, and the like; particularly preferredare the ammonium, potassium, sodium, calcium and magnesium salts.Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like, specifically such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. Many such salts are known in the art, as described in WO87/05297, Johnston et al., published Sep. 11, 1987 (incorporated byreference herein in its entirety).

As used herein, “C_(a) to C_(b)” or “C_(a-b)” in which “a” and “b” areintegers refer to the number of carbon atoms in the specified group.That is, the group can contain from “a” to “b”, inclusive, carbon atoms.Thus, for example, a “C₁ to C₄ alkyl” or “C₁₋₄ alkyl” group refers toall alkyl groups having from 1 to 4 carbons, that is, CH₃—, CH₃CH₂—,CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, (CH₃)₂CHCH₂—CH₃CH₂CH(CH₃)— and(CH₃)₃C—.

The term “halogen” or “halo,” as used herein, is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to any one of the radio-stableatoms of column 7 of the Periodic Table of the Elements, for example,fluorine, chlorine, bromine, or iodine.

As used herein, “alkyl” is a broad term, and is to be given its ordinaryand customary meaning to a person of ordinary skill in the art (and isnot to be limited to a special or customized meaning), and referswithout limitationto a straight or branched hydrocarbon chain that isfully saturated (i.e., contains no double or triple bonds). The alkylgroup may have 1 to 20 carbon atoms (whenever it appears herein, anumerical range such as “1 to 20” refers to each integer in the givenrange; for example, “1 to 20 carbon atoms” means that the alkyl groupmay consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., upto and including 20 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group may also be a medium size alkyl having 1 to9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to4 carbon atoms. The alkyl group may be designated as “C₁₋₄ alkyl” orsimilar designations. By way of example only, “C₁₋₄ alkyl” indicatesthat there are one to four carbon atoms in the alkyl chain, i.e., thealkyl chain is selected from the group consisting of methyl, ethyl,propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typicalalkyl groups include, but are in no way limited to, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, andthe like.

As used herein, “haloalkyl” is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitationto the alkyl moiety substituted with at leastone halo group. Examples of haloalkyl groups include, but are notlimited to, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CH₂CH₂C₁,or —CH₂CF₂CF₃.

As used herein, “alkoxy” is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitationto the formula —OR wherein R is an alkyl as isdefined above, such as “C₁₋₉ alkoxy”, including but not limited tomethoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,iso-butoxy, sec-butoxy, and tert-butoxy, and the like.

As used herein, “alkylthio” is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitationto the formula —SR wherein R is an alkyl as isdefined above, such as “C₁₋₉ alkylthio” and the like, including but notlimited to methylmercapto, ethylmercapto, n-propylmercapto,1-methylethylmercapto (isopropylmercapto), n-butylmercapto,iso-butylmercapto, sec-butylmercapto, tert-butylmercapto, and the like.

As used herein, “alkenyl” is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitationto a straight or branched hydrocarbon chaincontaining one or more double bonds. The alkenyl group may have 2 to 20carbon atoms, although the present definition also covers the occurrenceof the term “alkenyl” where no numerical range is designated. Thealkenyl group may also be a medium size alkenyl having 2 to 9 carbonatoms. The alkenyl group could also be a lower alkenyl having 2 to 4carbon atoms. The alkenyl group may be designated as “C₂₄ alkenyl” orsimilar designations. By way of example only, “C₂₋₄ alkenyl” indicatesthat there are two to four carbon atoms in the alkenyl chain, i.e., thealkenyl chain is selected from the group consisting of ethenyl,propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl,buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl,1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl,buta-1,2,-dienyl, and buta-1,2-dien-4-yl. Typical alkenyl groupsinclude, but are in no way limited to, ethenyl, propenyl, butenyl,pentenyl, and hexenyl, and the like.

As used herein, “alkynyl” is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitationto a straight or branched hydrocarbon chaincontaining one or more triple bonds. The alkynyl group may have 2 to 20carbon atoms, although the present definition also covers the occurrenceof the term “alkynyl” where no numerical range is designated. Thealkynyl group may also be a medium size alkynyl having 2 to 9 carbonatoms. The alkynyl group could also be a lower alkynyl having 2 to 4carbon atoms. The alkynyl group may be designated as “C₂₄ alkynyl” orsimilar designations. By way of example only, “C₂₄ alkynyl” indicatesthat there are two to four carbon atoms in the alkynyl chain, i.e., thealkynyl chain is selected from the group consisting of ethynyl,propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and2-butynyl. Typical alkynyl groups include, but are in no way limited to,ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.

The term “aromatic” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitationto a ring or ring system having a conjugated pielectron system and includes both carbocyclic aromatic (for example,phenyl) and heterocyclic aromatic groups (for example, pyridine). Theterm includes monocyclic or fused-ring polycyclic (i.e., rings whichshare adjacent pairs of atoms) groups provided that the entire ringsystem is aromatic.

As used herein, “aryl” is a broad term, and is to be given its ordinaryand customary meaning to a person of ordinary skill in the art (and isnot to be limited to a special or customized meaning), and referswithout limitationto an aromatic ring or ring system (i.e., two or morefused rings that share two adjacent carbon atoms) containing only carbonin the ring backbone. When the aryl is a ring system, every ring in thesystem is aromatic. The aryl group may have 6 to 18 carbon atoms,although the present definition also covers the occurrence of the term“aryl” where no numerical range is designated. In some embodiments, thearyl group has 6 to 10 carbon atoms. The aryl group may be designated as“C₆₋₁₀ aryl,” “C_(6 or 10) aryl,” or similar designations. Examples ofaryl groups include, but are not limited to, phenyl, naphthyl, azulenyl,and anthracenyl.

As used herein, “aryloxy” and “arylthio” are broad terms, and are to begiven their ordinary and customary meaning to a person of ordinary skillin the art (and are not to be limited to a special or customizedmeaning), and refer without limitationto RO— and RS—, in which R is anaryl as is defined above, such as “C₆₋₁₀ aryloxy” or “C₆₋₁₀ arylthio”and the like, including but not limited to phenyloxy.

As used herein, “aralkyl” or “arylalkyl” are broad terms, and are to begiven their ordinary and customary meaning to a person of ordinary skillin the art (and are not to be limited to a special or customizedmeaning), and refer without limitation to an aryl group connected, as asubstituent, via an alkylene group, such as “C₇₋₁₄ aralkyl” and thelike, including but not limited to benzyl, 2-phenylethyl,3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group isa lower alkylene group (i.e., a C₁₋₄ alkylene group).

As used herein, “alkylene” is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation toa branched, or straight chain fullysaturated di-radical chemical group containing only carbon and hydrogenthat is attached to the rest of the molecule via two points ofattachment (i.e., an alkanediyl). The alkylene group may have 1 to 20carbon atoms, although the present definition also covers the occurrenceof the term alkylene where no numerical range is designated. Thealkylene group may also be a medium size alkylene having 1 to 9 carbonatoms. The alkylene group could also be a lower alkylene having 1 to 4carbon atoms. The alkylene group may be designated as “C₁₋₄ alkylene” orsimilar designations. By way of example only, “C₁₋₄ alkylene” indicatesthat there are one to four carbon atoms in the alkylene chain, i.e., thealkylene chain is selected from the group consisting of methylene,ethylene, ethan-1,1-diyl, propylene, propan-1,1-diyl, propan-2,2-diyl,1-methyl-ethylene, butylene, butan-1,1-diyl, butan-2,2-diyl,2-methyl-propan-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene,1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

As used herein, “heteroaryl” is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitationto an aromatic ring or ring system (i.e., twoor more fused rings that share two adjacent atoms) that contain(s) oneor more heteroatoms, that is, an element other than carbon, includingbut not limited to, nitrogen, oxygen and sulfur, in the ring backbone.When the heteroaryl is a ring system, every ring in the system isaromatic. The heteroaryl group may have 5-18 ring members (i.e., thenumber of atoms making up the ring backbone, including carbon atoms andheteroatoms), although the present definition also covers the occurrenceof the term “heteroaryl” where no numerical range is designated. In someembodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7ring members including one or more nitrogen, oxygen and sulfur in thering backbone. The heteroaryl group may be designated as “5-7 memberedheteroaryl,” “5-10 membered heteroaryl,” or similar designations.Examples of heteroaryl rings include, but are not limited to, furyl,thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl,isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl,isoindolyl, and benzothienyl.

As used herein, “heteroaralkyl” or “heteroarylalkyl” are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to a heteroaryl groupconnected, as a substituent, via an alkylene group. Examples include butare not limited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl,thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, andimidazolylalkyl. In some cases, the alkylene group is a lower alkylenegroup (i.e., a C₁₋₄ alkylene group).

As used herein, “carbocyclyl” is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation toa non-aromatic cyclic ring or ring systemcontaining only carbon atoms in the ring system backbone. When thecarbocyclyl is a ring system, two or more rings may be joined togetherin a fused, bridged or spiro-connected fashion. Carbocyclyls may haveany degree of saturation provided that at least one ring in a ringsystem is not aromatic. Thus, carbocyclyls include cycloalkyls,cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20carbon atoms, although the present definition also covers the occurrenceof the term “carbocyclyl” where no numerical range is designated. Thecarbocyclyl group may also be a medium size carbocyclyl having 3 to 10carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3to 6 carbon atoms. The carbocyclyl group may be designated as “C₃₋₆carbocyclyl” or similar designations. Examples of carbocyclyl ringsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, ,3-dihydro-indene, bicycle[2.2.2] octanyl,adamantyl, and spiro [4.4] nonanyl.

As used herein, “cycloalkyl” is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a fully saturated carbocyclyl ring or ringsystem. Examples include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

As used herein, “cycloalkenyl” is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation toa carbocyclyl ring or ring system having atleast one double bond, wherein no ring in the ring system is aromatic.An example is cyclohexenyl.

As used herein, “heterocyclyl” is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a non-aromatic cyclic ring or ring systemcontaining at least one heteroatom in the ring backbone. Heterocyclylsmay be joined together in a fused, bridged or spiro-connected fashion.Heterocyclyls may have any degree of saturation provided that at leastone ring in the ring system is not aromatic. The heteroatom(s) may bepresent in either a non-aromatic or aromatic ring in the ring system.The heterocyclyl group may have 3 to 20 ring members (i.e., the numberof atoms making up the ring backbone, including carbon atoms andheteroatoms), although the present definition also covers the occurrenceof the term “heterocyclyl” where no numerical range is designated. Theheterocyclyl group may also be a medium size heterocyclyl having 3 to 10ring members. The heterocyclyl group could also be a heterocyclyl having3 to 6 ring members. The heterocyclyl group may be designated as “3-6membered heterocyclyl” or similar designations. In preferred sixmembered monocyclic heterocyclyls, the heteroatom(s) are selected fromone up to three of O, N or S, and in preferred five membered monocyclicheterocyclyls, the heteroatom(s) are selected from one or twoheteroatoms selected from O, N, or S. Examples of heterocyclyl ringsinclude, but are not limited to, azepinyl, acridinyl, carbazolyl,cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl,oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl,dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl,4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl,1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl,1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl,1,3 -dioxolyl, 1,3 -dioxolanyl, 1,3 -dithiolyl, 1,3 -dithiolanyl,isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl,thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl,dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

As used herein, “acyl” is a broad term, and is to be given its ordinaryand customary meaning to a person of ordinary skill in the art (and isnot to be limited to a special or customized meaning), and referswithout limitationto —C(═O)R, wherein R is hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein.Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, andacryl.

As used herein, “O-carboxy” group is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitationto a “—OC(═O)R” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein.

As used herein, “C-carboxy” group is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitationto a “C(═O)OR” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein. A non-limiting example includes carboxyl (i.e.,—C(═O)OH).

As used herein, “cyano” group is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitationto a “—CN” group.

As used herein, “cyanato” group is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitationto an “—OCN” group.

As used herein, “isocyanato” group is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitationto a “—NCO” group.

As used herein, “thiocyanato” group is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitationto a “—SCN” group.

As used herein, “isothiocyanato” group is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitationto an “ —NCS” group.

As used herein, “sulfinyl” group is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitationto an “—S(═O)R” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein.

As used herein, “sulfonyl” group is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitationto an “—SO₂R” group in which R is selected fromhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein.

As used herein, “S-sulfonamido” group is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitationto a “—SO₂NR_(A)R_(B)” group inwhich R^(A) and R^(B) are each independently selected from hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as definedherein.

As used herein, “N-sulfonamido” group is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitationto a “—N(R_(A))SO₂R_(B)” group inwhich R^(A) and R_(b) are each independently selected from hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as definedherein.

As used herein, “O-carbamyl” group is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitationto a “—OC(═O)NR_(A)R_(B)” group in which R^(A)and R^(B) are each independently selected from hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein.

As used herein, “N-carbamyl” group is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitationto an “—N(R_(A))C(═O)OR_(B)” group in whichR^(A) and R^(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

As used herein, “O-thiocarbamyl” group is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitationto a “—OC(═S)NR_(A)R_(B)” groupin which R^(A) and R^(B) are each independently selected from hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as definedherein.

As used herein, “N-thiocarbamyl” group is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitationto an “—N(R_(A))C(═S)OR_(B)”group in which R^(A) and R^(B) are each independently selected fromhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein.

As used herein, “C-amido” group is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitationto a “—C(═O)NR_(A)R_(B)” group in which R^(A)and R^(B) are each independently selected from hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein.

As used herein, “N-amido” group is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitationto a “—N(R_(A))C(═O)R_(B)” group in which R^(A)and R^(B) are each independently selected from hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein.

As used herein, “amino” group is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitationto a “—NR_(A)R_(B)” group in which R^(A) andR^(B) are each independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein. Anon-limiting example includes free amino (i.e., —NH₂).

As used herein, “aminoalkyl” group is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitationto an amino group connected via an alkylenegroup.

As used herein, “alkoxyalkyl” group is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitationto an alkoxy group connected via an alkylenegroup, such as a “C₂₋₈ alkoxyalkyl” and the like.

As used herein, “haloalkoxy” refers to the formula —OR wherein R is ahaloalkyl as defined above, such as —CF₃, —CHF₂, —CH₂F, —CH₂CF₃,—CH₂CHF₂, —CH₂CH₂F, —CH₂CH₂Cl, or —CH₂CF₂CF₃.

As used herein, the term “substituted”, as in a substituted group, is abroad term, and is to be given its ordinary and customary meaning to aperson of ordinary skill in the art (and is not to be limited to aspecial or customized meaning), and refers without limitation to a groupthat is derived from the unsubstituted parent group in which there hasbeen an exchange of one or more hydrogen atoms for another atom orgroup. Unless otherwise indicated, when a group is deemed to be“substituted,” it is meant that the group is substituted with one ormore substituents independently selected from C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₇ carbocyclyl (optionally substituted withhalo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy),C₃-C₇-carbocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10membered heterocyclyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 memberedheterocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), aryl (optionallysubstituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, andC₁-C₆ haloalkoxy), aryl(C₁-C₆)alkyl (optionally substituted with halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10membered heteroaryl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 memberedheteroaryl(C₁-C₆)alkyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), halo, cyano,hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl (i.e., ether), aryloxy,sulfhydryl (mercapto), halo(C₁-C₆)alkyl (for example, —CF₃),halo(C₁-C₆)alkoxy (for example, —OCF₃), C₁-C₆ alkylthio, arylthio,amino, amino(C₁-C₆)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato,isothiocyanato, sulfinyl, sulfonyl, and oxo (═O).

It is to be understood that certain radical naming conventions caninclude either a mono-radical or a di-radical, depending on the context.For example, where a substituent requires two points of attachment tothe rest of the molecule, it is understood that the substituent is adi-radical. For example, a substituent identified as alkyl that requirestwo points of attachment includes di-radicals such as —CH₂—, —CH₂CH₂—,—CH₂CH(CH₃)CH₂—, and the like. Other radical naming conventions clearlyindicate that the radical is a di-radical such as “alkylene.”

When two R groups are said to form a ring (for example, a heterocyclyl,or heteroaryl ring) “together with the atom to which they are attached,”it is meant that the collective unit of the atom and the two R groupsare the recited ring. The ring is not otherwise limited by thedefinition of each R group when taken individually.

Similarly, when two “adjacent” R groups are said to form a ring“together with the atoms to which they are attached,” it is meant thatthe collective unit of the atoms, intervening bonds, and the two Rgroups are the recited ring. For example, when the followingsubstructure is present:

and R⁵ and R⁶ are defined as hydrogen or R^(A), where adjacent R^(A)together with the atoms to which they are attached form a heterocyclyl,or heteroaryl ring, it is meant that R⁵ and R⁶ can be selected fromhydrogen or R^(A), or alternatively, the substructure has structure:

where A is a heterocyclyl, or heteroaryl ring containing the depicteddouble bond.

Wherever a substituent is depicted as a di-radical (i.e., has two pointsof attachment to the rest of the molecule), it is to be understood thatthe substituent can be attached in any directional configuration unlessotherwise indicated. Thus, for example, a substituent depicted as -AE-or

includes the substituent being oriented such that the A is attached atthe leftmost attachment point of the molecule as well as the case inwhich A is attached at the rightmost attachment point of the molecule.

The term “Subject” as used herein, is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a human or a non-human mammal, for example,a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-humanprimate or a bird, for example, a chicken, as well as any othervertebrate or invertebrate.

The term “mammal” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), and isused in its usual biological sense. Thus, it specifically includes, butis not limited to, primates, including simians (chimpanzees, apes,monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs,cats, rodents, rats, mice guinea pigs, or the like.

An “effective amount” or a “therapeutically effective amount” are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to anamount of a therapeutic agent that is effective to relieve, to someextent, or to reduce the likelihood of onset of, one or more of thesymptoms of a disease or condition, and includes curing a disease orcondition. “Curing” means that the symptoms of a disease or conditionare eliminated; however, certain long-term or permanent effects mayexist even after a cure is obtained (such as extensive tissue damage).

“Treat,” “treatment,” or “treating,” as used herein are broad terms, andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitationto administering acompound or pharmaceutical composition to a subject for prophylacticand/or therapeutic purposes. The term “prophylactic treatment” refers totreating a subject who does not yet exhibit symptoms of a disease orcondition, but who is susceptible to, or otherwise at risk of, aparticular disease or condition, whereby the treatment reduces thelikelihood that the patient will develop the disease or condition. Theterm “therapeutic treatment” refers to administering treatment to asubject already suffering from a disease or condition.

Administration and Pharmaceutical Compositions

Administration of any compounds or pharmaceutically active substancesdisclosed herein or any pharmaceutically acceptable salts thereof can beadministered via any of the accepted modes of administration for agentsthat serve similar utilities including, but not limited to, orally,subcutaneously, intravenously, intranasally, topically, transdermally,intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,rectally, or intraocularly.

The compounds useful as described above can be formulated intopharmaceutical compositions for use in treatment of these conditions.Standard pharmaceutical formulation techniques are used, such as thosedisclosed in Remington's The Science and Practice of Pharmacy, 21st Ed.,Lippincott Williams & Wilkins (2005), incorporated herein by referencein its entirety. Accordingly, some embodiments include pharmaceuticalcompositions comprising: (a) a safe and therapeutically effective amountof a compound described herein (including enantiomers, diastereoisomers,tautomers, polymorphs, and solvates thereof), or pharmaceuticallyacceptable salts thereof; and (b) a pharmaceutically acceptable carrier,diluent, excipient or combination thereof.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions iscontemplated. In addition, various adjuvants such as are commonly usedin the art may be included. Considerations for the inclusion of variouscomponents in pharmaceutical compositions are described, for example, inGilman et al. (Eds.) (1990); Goodman and Gilman's: The PharmacologicalBasis of Therapeutics, 8th Ed., Pergamon Press, which is incorporatedherein by reference in its entirety.

Some examples of substances, which can serve aspharmaceutically-acceptable carriers or components thereof, are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents;flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

The compositions described herein are preferably provided in unit dosageform. As used herein, a “unit dosage form” is a composition containingan amount of a compound that is suitable for administration to ananimal, preferably mammal subject, in a single dose, according to goodmedical practice. The preparation of a single or unit dosage formhowever, does not imply that the dosage form is administered once perday or once per course of therapy. Such dosage forms are contemplated tobe administered once, twice, thrice or more per day and may beadministered as infusion over a period of time (for example, from about30 minutes to about 2-6 hours), or administered as a continuousinfusion, and may be given more than once during a course of therapy,though a single administration is not specifically excluded. The skilledartisan will recognize that the formulation does not specificallycontemplate the entire course of therapy and such decisions are left forthose skilled in the art of treatment rather than formulation.

The compositions useful as described above may be in any of a variety ofsuitable forms for a variety of routes for administration, for example,for oral, nasal, rectal, topical (including transdermal), ocular,intracerebral, intracranial, intrathecal, intra-arterial, intravenous,intramuscular, or other parental routes of administration. The skilledartisan will appreciate that oral and nasal compositions includecompositions that are administered by inhalation, and made usingavailable methodologies. Depending upon the particular route ofadministration desired, a variety of pharmaceutically-acceptablecarriers well-known in the art may be used. Pharmaceutically-acceptablecarriers include, for example, solid or liquid fillers, diluents,hydrotropies, surface-active agents, and encapsulating substances.Optional pharmaceutically-active materials may be included, which do notsubstantially interfere with the inhibitory activity of the compound.The amount of carrier employed in conjunction with the compound issufficient to provide a practical quantity of material foradministration per unit dose of the compound. Techniques andcompositions for making dosage forms useful in the methods describedherein are described in the following references, all incorporated byreference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10(Banker & Rhodes, editors, 2002); Lieberman et al., PharmaceuticalDosage Forms: Tablets (1989); and Ansel, Introduction to PharmaceuticalDosage Forms 8th Edition (2004).

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. Tablets can be compressed,tablet triturates, enteric-coated, sugar-coated, film-coated, ormultiple-compressed, containing suitable binders, lubricants, diluents,disintegrating agents, coloring agents, flavoring agents, flow-inducingagents, and melting agents. Liquid oral dosage forms include aqueoussolutions, emulsions, suspensions, solutions and/or suspensionsreconstituted from non-effervescent granules, and effervescentpreparations reconstituted from effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, melting agents, coloring agents and flavoringagents.

The pharmaceutically-acceptable carriers suitable for the preparation ofunit dosage forms for peroral administration is well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical, and can be readily made by aperson skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; typicalwetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragitcoatings, waxes and shellac.

Compositions described herein may optionally include other drug actives.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

A liquid composition, which is formulated for topical ophthalmic use, isformulated such that it can be administered topically to the eye. Thecomfort may be maximized as much as possible, although sometimesformulation considerations (for example drug stability) may necessitateless than optimal comfort. In the case that comfort cannot be maximized,the liquid may be formulated such that the liquid is tolerable to thepatient for topical ophthalmic use. Additionally, an ophthalmicallyacceptable liquid may either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions may preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositionsdisclosed herein include, but are not limited to, benzalkonium chloride,PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations disclosed herein. These vehicles include, but are notlimited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose,poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purifiedwater.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. For manycompositions, the pH will be between 4 and 9. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant includes,but is not limited to, sodium metabisulfite, sodium thiosulfate,acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

Other excipient components, which may be included in the ophthalmicpreparations, are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,co-solvent, emulsifier, penetration enhancer, preservative system, andemollient.

For intravenous administration, the compounds and compositions describedherein may be dissolved or dispersed in a pharmaceutically acceptablediluent, such as a saline or dextrose solution. Suitable excipients maybe included to achieve the desired pH, including but not limited toNaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In variousembodiments, the pH of the final composition ranges from 2 to 8, orpreferably from 4 to 7. Antioxidant excipients may include sodiumbisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate,thiourea, and EDTA. Other non-limiting examples of suitable excipientsfound in the final intravenous composition may include sodium orpotassium phosphates, citric acid, tartaric acid, gelatin, andcarbohydrates such as dextrose, mannitol, and dextran. Furtheracceptable excipients are described in Powell, et al., Compendium ofExcipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998,52 238-311 and Nema et al., Excipients and Their Role in ApprovedInjectable Products: Current Usage and Future Directions, PDA J PharmSci and Tech 2011, 65 287-332, both of which are incorporated herein byreference in their entirety. Antimicrobial agents may also be includedto achieve a bacteriostatic or fungistatic solution, including but notlimited to phenylmercuric nitrate, thimerosal, benzethonium chloride,benzalkonium chloride, phenol, cresol, and chlorobutanol.

The compositions for intravenous administration may be provided tocaregivers in the form of one more solids that are reconstituted with asuitable diluent such as sterile water, saline or dextrose in watershortly prior to administration. In other embodiments, the compositionsare provided in solution ready to administer parenterally. In stillother embodiments, the compositions are provided in a solution that isfurther diluted prior to administration. In embodiments that includeadministering a combination of a compound described herein and anotheragent, the combination may be provided to caregivers as a mixture, orthe caregivers may mix the two agents prior to administration, or thetwo agents may be administered separately.

The actual dose of the active compounds described herein depends on thespecific compound, and on the condition to be treated; the selection ofthe appropriate dose is well within the knowledge of the skilledartisan. In some embodiments, a daily dose may be from about 0.25 mg/kgto about 120 mg/kg or more of body weight, from about 0.5 mg/kg or lessto about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of bodyweight, or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus,for administration to a 70 kg person, the dosage range would be fromabout 17 mg per day to about 8000 mg per day, from about 35 mg per dayor less to about 7000 mg per day or more, from about 70 mg per day toabout 6000 mg per day, from about 100 mg per day to about 5000 mg perday, or from about 200 mg to about 3000 mg per day.

Methods of Treatment

Some embodiments include methods of treating an aneurysm with andcompositions comprising compounds described herein. Some methods includeadministering a compound, composition, pharmaceutical compositiondescribed herein to a subject in need thereof. In some embodiments, asubject can be an animal, for example, a mammal, a human. In someembodiments, the subject is a human.

Further embodiments include administering a combination of compounds toa subject in need thereof. A combination can include a compound,composition, pharmaceutical composition described herein with anadditional medicament.

Some embodiments include co-administering a compound, composition,and/or pharmaceutical composition described herein, with an additionalmedicament. By “co-administration,” it is meant that the two or moreagents may be found in the patient's bloodstream at the same time,regardless of when or how they are actually administered. In oneembodiment, the agents are administered simultaneously. In one suchembodiment, administration in combination is accomplished by combiningthe agents in a single dosage form. In another embodiment, the agentsare administered sequentially. In one embodiment the agents areadministered through the same route, such as orally. In anotherembodiment, the agents are administered through different routes, suchas one being administered orally and another being administeredintravenously.

Examples of additional medicaments include collagen crosslinking agents,such as glutaraldehyde, genipin acyl azide, and/or epoxyamine.

To further illustrate this invention, the following examples areincluded. The examples should not, of course, be construed asspecifically limiting the invention. Variations of these examples withinthe scope of the claims are within the purview of one skilled in the artand are considered to fall within the scope of the invention asdescribed, and claimed herein. The reader will recognize that theskilled artisan, armed with the present disclosure, and skill in the artis able to prepare and use the invention without exhaustive examples.

Although the invention has been described with reference to embodimentsand examples, it should be understood that numerous and variousmodifications can be made without departing from the spirit of theinvention. Accordingly, the invention is limited only by the followingclaims.

It is understood that this disclosure, in many respects, is onlyillustrative of the numerous alternative device embodiments. Changes maybe made in the details, particularly in matters of shape, size, materialand arrangement of various device components without exceeding the scopeof the various embodiments of the invention. Those skilled in the artwill appreciate that the exemplary embodiments and descriptions thereofare merely illustrative of the invention as a whole. While severalprinciples of the invention are made clear in the exemplary embodimentsdescribed above, those skilled in the art will appreciate thatmodifications of the structure, arrangement, proportions, elements,materials and methods of use, may be utilized in the practice of theinvention, and otherwise, which are particularly adapted to specificenvironments and operative requirements without departing from the scopeof the invention. In addition, while certain features and elements havebeen described in connection with particular embodiments, those skilledin the art will appreciate that those features and elements can becombined with the other embodiments disclosed herein.

When a feature or element is herein referred to as being “on” anotherfeature or element, it can be directly on the other feature or elementor intervening features and/or elements may also be present. Incontrast, when a feature or element is referred to as being “directlyon” another feature or element, there are no intervening features orelements present. It will also be understood that when a feature orelement is referred to as being “connected”, “attached” or “coupled” toanother feature or element, it can be directly connected, attached orcoupled to the other feature or element or intervening features orelements may be present. In contrast, when a feature or element isreferred to as being “directly connected”, “directly attached” or“directly coupled” to another feature or element, there are nointervening features or elements present. Although described or shownwith respect to one embodiment, the features and elements so describedor shown can apply to other embodiments. It will also be appreciated bythose of skill in the art that references to a structure or feature thatis disposed “adjacent” another feature may have portions that overlap orunderlie the adjacent feature.

Terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention.For example, as used herein, the singular forms “a”, “an” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It will be further understood that the terms“comprises” and/or “comprising,” when used in this specification,specify the presence of stated features, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, steps, operations, elements, components, and/orgroups thereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items and may beabbreviated as “/”.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if a device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of over and under. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

Although the terms “first” and “second” may be used herein to describevarious features/elements (including steps), these features/elementsshould not be limited by these terms, unless the context indicatesotherwise. These terms may be used to distinguish one feature/elementfrom another feature/element. Thus, a first feature/element discussedbelow could be termed a second feature/element, and similarly, a secondfeature/element discussed below could be termed a first feature/elementwithout departing from the teachings of the present invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising” means various components can be co-jointlyemployed in the methods and articles (for example, compositions andapparatuses including device and methods). For example, the term“comprising” will be understood to imply the inclusion of any statedelements or steps but not the exclusion of any other elements or steps.

As used herein in the specification and claims, including as used in theexamples and unless otherwise expressly specified, all numbers may beread as if prefaced by the word “about” or “approximately,” even if theterm does not expressly appear. The phrase “about” or “approximately”may be used when describing magnitude and/or position to indicate thatthe value and/or position described is within a reasonable expectedrange of values and/or positions. For example, a numeric value may havea value that is +/−0.1% of the stated value (or range of values), +/−1%of the stated value (or range of values), +/−2% of the stated value (orrange of values), +/−5% of the stated value (or range of values), +/−10%of the stated value (or range of values), etc. Any numerical valuesgiven herein should also be understood to include about or approximatelythat value, unless the context indicates otherwise. For example, if thevalue “10” is disclosed, then “about 10” is also disclosed. Anynumerical range recited herein is intended to include all sub-rangessubsumed therein. It is also understood that when a value is disclosedthat “less than or equal to” the value, “greater than or equal to thevalue” and possible ranges between values are also disclosed, asappropriately understood by the skilled artisan. For example, if thevalue “X” is disclosed the “less than or equal to X” as well as “greaterthan or equal to X” (for example, where X is a numerical value) is alsodisclosed. It is also understood that the throughout the application,data is provided in a number of different formats, and that this data,represents endpoints and starting points, and ranges for any combinationof the data points. For example, if a particular data point “10” and aparticular data point “15” are disclosed, it is understood that greaterthan, greater than or equal to, less than, less than or equal to, andequal to 10 and 15 are considered disclosed as well as between 10 and15. It is also understood that each unit between two particular unitsare also disclosed. For example, if 10 and 15 are disclosed, then 11,12, 13, and 14 are also disclosed.

Although various illustrative embodiments are described above, any of anumber of changes may be made to various embodiments without departingfrom the scope of the invention as described by the claims. For example,the order in which various described method steps are performed mayoften be changed in alternative embodiments, and in other alternativeembodiments one or more method steps may be skipped altogether. Optionalfeatures of various device and system embodiments may be included insome embodiments and not in others. Therefore, the foregoing descriptionis provided primarily for exemplary purposes and should not beinterpreted to limit the scope of the invention as it is set forth inthe claims.

The examples and illustrations included herein show, by way ofillustration and not of limitation, specific embodiments in which thesubject matter may be practiced. As mentioned, other embodiments may beutilized and derived there from, such that structural and logicalsubstitutions and changes may be made without departing from the scopeof this disclosure. Such embodiments of the inventive subject matter maybe referred to herein individually or collectively by the term“invention” merely for convenience and without intending to voluntarilylimit the scope of this application to any single invention or inventiveconcept, if more than one is, in fact, disclosed. Thus, althoughspecific embodiments have been illustrated and described herein, anyarrangement calculated to achieve the same purpose may be substitutedfor the specific embodiments shown. This disclosure is intended to coverany and all adaptations or variations of various embodiments.Combinations of the above embodiments, and other embodiments notspecifically described herein, will be apparent to those of skill in theart upon reviewing the above description

What is claimed is:
 1. A device for treating an aneurysm, comprising: ashaft; a first balloon attached to a first end of the shaft; and asecond balloon attached to a second end of the shaft, the second ballooncomprising a plurality of pores for delivering a therapeutic agent tothe aneurysm.
 2. The device of claim 1, wherein the first balloon ispositioned near a distal end of the shaft for anchoring the device andstopping downstream blood flow, and wherein the second balloon ispositioned near a proximal end of the shaft for stopping retrogradeblood flow and/or for displacing blood from an aneurysmal sac.
 3. Thedevice of claim 1, wherein the second balloon is positioned near adistal end of the shaft for anchoring the device and stopping downstreamblood flow, and wherein the first balloon is positioned near a proximalend of the shaft for stopping retrograde blood flow.
 4. The device ofclaim 1, further comprising a third balloon positioned within the secondballoon for expanding the second balloon, the third balloon expandablewith saline.
 5. A kit for treating aneurysms, comprising: the device ofclaim 1; purified pentagalloyl glucose (PGG) having a purity greaterthan or equal to 99%; and a hydrolyzer.
 6. A catheter for treating ananeurysm, the catheter comprising: an elongate body configured to beintroduced into a blood vessel, the elongate body having a proximal end,a distal end, and a main shaft having a lumen extending therethrough; afirst inflatable balloon coupled to the distal end of the elongate body,the first inflatable balloon having an interior volume in fluidcommunication with a first inflation lumen; and a second inflatableballoon coupled to the elongate body proximally to the first inflatableballoon, the second inflatable balloon having an interior volume influid communication with a second inflation lumen, wherein the secondinflatable balloon circumferentially surrounds the elongate body, andwherein the second inflatable balloon comprises a plurality of poresdisposed on a surface of the second inflatable balloon configured toplace the interior volume of the second inflatable balloon in fluidcommunication with an intravascular environment of the blood vessel. 7.The catheter of claim 6, wherein the main shaft extends through thesecond inflatable balloon and the distal end of the main shaft forms thedistal end of the elongate body.
 8. The catheter of claim 7, wherein thefirst inflation lumen and the second inflation lumen are formed withinthe main shaft.
 9. The catheter of claim 6, wherein the elongate bodyfurther comprises a second shaft having a lumen extending therethrough,the second shaft being disposed within the lumen of the main shaft, thefirst inflatable balloon being coupled to a distal end of the secondshaft and the second inflatable balloon being coupled to a distal end ofthe main shaft.
 10. The catheter of claim 9, wherein the lumen of themain shaft is the second inflation lumen.
 11. The catheter of claim 9,wherein the lumen of the second shaft is the first inflation lumen. 12.A kit for treating aneurysms, comprising: the catheter of claim 6;purified pentagalloyl glucose (PGG) having a purity greater than orequal to 99%; and a hydrolyzer.
 13. The kit of claim 12, wherein thehydrolyzer is ethanol.
 14. The kit of claim 12, wherein the hydrolyzeris dimethyl sulfoxide (DMSO) or contrast media.
 15. A method fortreating an aneurysm in a blood vessel of a patient, comprising:positioning a first balloon upstream the aneurysm; positioning a secondballoon adjacent the aneurysm; inflating the first balloon to occludedownstream blood flow; expanding the second balloon to occluderetrograde blood flow and/or displace blood from the aneurysmal sac; anddelivering a therapeutic agent to the aneurysm through pores in thesecond balloon.
 16. The method of claim 15, wherein expanding the secondballoon comprises introducing an inflation fluid into an interior volumeof the second balloon.
 17. The method of claim 15, wherein deliveringthe therapeutic agent comprises introducing a solution comprising thetherapeutic agent into an interior volume of the second balloon, theintroduction of the solution being configured to expand and/or maintainan expanded state of the second balloon.
 18. The method of claim 15,wherein inflating the first balloon and expanding the second ballooncreates a sealed volume within the blood vessel between the firstballoon and the second balloon.
 19. The method of claim 18, whereindelivering the therapeutic agent comprises introducing the therapeuticagent into the sealed volume.
 20. The method of claim 15, wherein thetherapeutic agent comprises pentagalloyl glucose (PGG).